Spectrum and functions of ion channels and transporters in osteoclasts

Abstract

Osteoclasts are essential for bone resorption and interact with osteoblasts during bone remodeling. Ion channels and transporters located in the ruffled border or intracellular vesicles coordinate the transport of various ions and substrates, which is fundamental to the primary functions of osteoclasts. Numerous channels and transporters are implicated in bone metabolic disorders and genetic diseases. Among these, the voltage-gated chloride channel 7 (ClC-7) and vacuolar proton ATPases (V-ATPase) represent the most well-characterized examples in osteoclasts. Using the classification system of the Transporter Classification Database, we reviewed nearly 90 osteoclastic ion channels and transporters, categorizing them into six groups: ATPases, cation channels, anion channels, complex transporters, organic substance transporters, and ATP-binding cassette transporters. We summarized recent advances in their subcellular localization, transported substrates, associated diseases, and physiological roles in relevant biological functions and signaling pathways. Notably, transporters for hydrogen, chloride, phosphate, and calcium are particularly critical for osteoclast function. We also reviewed therapeutic candidates targeting these ion channels and discussed strategies for their future development. As transcriptome and other advanced techniques have identified more channels and transporters in osteoclasts, the diversity and unexplored functions of these molecules may exceed previous understanding. Increased attention to their widespread distributions and interactions could reveal new therapeutic targets for osteoclast-related and other bone disorders.

References

[1] Williams AJet al. . Iodothyronine deiodinase enzyme activities in bone. Bone. 2008, 43: 126-134.

[2] Komarova SV, Dixon SJ, Sims SM. Osteoclast ion channels: potential targets for antiresorptive drugs. Curr. Pharm. Des.. 2001, 7: 637-654.

[3] Coxon FP, Taylor A. Vesicular trafficking in osteoclasts. Semin. Cell Dev. Biol.. 2008, 19: 424-433.

[4] Francis MJOet al. . ATPase pumps in osteoclasts and osteoblasts. Int. J. Biochem. Cell Biol.. 2002, 34: 459-476.

[5] Henriksen Ket al. . Ion transporters involved in acidification of the resorption lacuna in osteoclasts. Calcif. Tissue Int.. 2008, 83: 230-242.

[6] Graves AR, Curran PK, Smith CL, Mindell JA. The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature. 2008, 453: 788-792.

[7] Michalak, A., Wdowikowska, A. & Janicka, M. Plant plasma membrane proton pump: one protein with multiple functions. Cells. 11, 4052 (2022).

[8] Kuhlbrandt W. Structure and mechanisms of F-Type ATP synthases. Annu. Rev. Biochem.. 2019, 88: 515-549.

[9] Vasanthakumar T, Rubinstein JL. Structure and roles of V-type ATPases. Trends Biochem.Sci.. 2020, 45: 295-307.

[10] Duan X, Yang S, Zhang L, Yang T. V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics. 2018, 8: 5379-5399.

[11] Hemken P, Guo XL, Wang ZQ, Zhang K, Gluck S. Immunologic evidence that vacuolar H⁺ ATPases with heterogeneous forms of Mr = 31 000 subunit have different membrane distributions in mammalian kidney. J. Biol. Chem.. 1992, 267: 9948-9957.

[12] Stransky L, Cotter K, Forgac M. The function of V-ATPases in cancer. Physiol. Rev.. 2016, 96: 1071-1091.

[13] Bouche Vet al. . Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway. Autophagy. 2016, 12: 484-498.

[14] Lee BS, Gluck SL, Holliday LS. Interaction between vacuolar H⁺-ATPase and microfilaments during osteoclast activation. J. Biol. Chem.. 1999, 274: 29164-29171.

[15] Lee Set al. . v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat. Med.. 2006, 12: 1403-1409.

[16] Wu H, Xu G, Li Y. Atp6v0d2 is an essential component of the osteoclast-specific proton pump that mediates extracellular acidification in bone resorption. J. Bone. Miner. Res.. 2009, 24: 871-885.

[17] Sun-Wada Get al. . Acidic endomembrane organelles are required for mouse postimplantation development. Dev. Biol.. 2000, 228: 315-325.

[18] Bhargava Aet al. . Osteopetrosis mutation R444L causes endoplasmic reticulum retention and misprocessing of vacuolar H⁺-ATPase a3 subunit. J. Biol. Chem.. 2012, 287: 26829-26839.

[19] Xue Yet al. . Dental abnormalities caused by novel compound heterozygous CTSK mutations. J. Dent. Res.. 2015, 94: 674-681.

[20] Qin Aet al. . V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int. J. Biochem. Cell Biol.. 2012, 44: 1422-1435.

[21] Yang Det al. . V-ATPase subunit ATP6AP1 (Ac45) regulates osteoclast differentiation, extracellular acidification, lysosomal trafficking, and protease exocytosis in osteoclast-mediated bone resorption. J. Bone. Miner. Res.. 2012, 27: 1695-1707.

[22] Chen Let al. . Osteoclastic ATP6AP2 maintains beta-catenin levels to prevent hyper-osteoclastic activation and trabecular bone-loss. J. Bone. Miner. Res.. 2024, 39: 1821-1834.

[23] Perdu Bet al. . Refined genomic localization of the genetic lesion in the osteopetrosis (op) rat and exclusion of three positional and functional candidate genes, Clcn7, Atp6v0c, and Slc9a3r2. Calcif. Tissue Int.. 2009, 84: 355-360.

[24] Mattison KAet al. . ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy. Brain. 2023, 146: 1357-1372.

[25] Kim Tet al. . ATP6v0d2 deficiency increases bone mass, but does not influence ovariectomy-induced bone loss. Biochem. Biophys. Res. Commun.. 2010, 403: 73-78.

[26] Guo Det al. . Fluid shear stress changes cell morphology and regulates the expression of ATP6V1A and TCIRG1 mRNA in rat osteoclasts. Mol. Med. Rep.. 2010, 3: 173-178

[27] Lee BS, Holliday LS, Ojikutu B, Krits I, Gluck SL. Osteoclasts express the B2 isoform of vacuolar H⁺-ATPase intracellularly and on their plasma membranes. Am. J. Physiol.. 1996, 270: C382-C388.

[28] Bartkiewicz M, Hernando N, Reddy SV, Roodman GD, Baron R. Characterization of the osteoclast vacuolar H⁺-ATPase B-subunit. Gene. 1995, 160: 157-164.

[29] Chen Set al. . Vacuolar H⁺-ATPase binding to microfilaments: regulation in response to phosphatidylinositol 3-kinase activity and detailed characterization of the actin-binding site in subunit B. J. Biol. Chem.. 2004, 279: 7988-7998.

[30] Feng Set al. . Atp6v1c1 is an essential component of the osteoclast proton pump and in F-actin ring formation in osteoclasts. Biochem. J.. 2009, 417: 195-203.

[31] McConnell Met al. . Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity. Oncotarget. 2017, 8: 47675-47690.

[32] Tan Let al. . Bivariate genome-wide association study implicates ATP6V1G1 as a novel pleiotropic locus underlying osteoporosis and age at menarche. J. Clin. Endocrinol. Metab.. 2015, 100: E1457-E1466.

[33] Duan Xet al. . Deficiency of ATP6V1H causes bone loss by inhibiting bone resorption and bone formation through the TGF-beta1 pathway. Theranostics. 2016, 6: 2183-2195.

[34] Yang Set al. . ATP6V1H deficiency impairs glucose tolerance by augmenting endoplasmic reticulum stress in high-fat diet-fed mice. Arch. Biochem. Biophys.. 2022, 716: 109116.

[35] Zhao, Z., Wang, X., Ma, Y. & Duan, X. Atp6v1h deficiency blocks bone loss in simulated microgravity mice through the Fos-Jun-Src-Integrin pathway. Int. J. Mol. Sci. 25, 637 (2024).

[36] Jonckheere AI, Smeitink JAM, Rodenburg RJT. Mitochondrial ATP synthase: architecture, function and pathology. J. Inherit. Metab. Dis.. 2012, 35211-225.

[37] Capaldi RA, Aggeler R, Turina P, Wilkens S. Coupling between catalytic sites and the proton channel in F1F0-type ATPases. Trends Biochem.Sci.. 1994, 19: 284-289.

[38] Xu Yet al. . Targeted inhibition of ATP5B gene prevents bone erosion in collagen-induced arthritis by inhibiting osteoclastogenesis. Pharmacol. Res.. 2021, 165: 105458.

[39] Griffiths EJ, Rutter GA. Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells. Biochim. Biophys. Acta. 2009, 17871324-1333.

[40] Bagur R, Hajnoczky G. Intracellular Ca²⁺ sensing: its role in calcium homeostasis and signaling. Mol. Cell.. 2017, 66: 780-788.

[41] Di Leva F, Domi T, Fedrizzi L, Lim D, Carafoli E. The plasma membrane Ca²⁺ ATPase of animal cells: structure, function and regulation. Arch. Biochem. Biophys.. 2008, 476: 65-74.

[42] Yang Yet al. . Alteration of RANKL-induced osteoclastogenesis in primary cultured osteoclasts from SERCA2^+/- mice. J. Bone. Miner. Res.. 2009, 24: 1763-1769.

[43] Wei Xet al. . Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2. Embo Mol. Med.. 2022, 14. e15373

[44] Mentaverri R, Kamel S, Brazier M. Involvement of capacitive calcium entry and calcium store refilling in osteoclastic survival and bone resorption process. Cell Calcium. 2003, 34: 169-175.

[45] Kim HJet al. . Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival. J. Cell. Biol.. 2012, 199: 1145-1158.

[46] Go W, Korzh V. Plasma membrane Ca²⁺ ATPase Atp2b1a regulates bone mineralization in zebrafish. Bone. 2013, 54: 48-57.

[47] Perez-Canamas Aet al. . Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease. Mol. Psychiatry.. 2017, 22: 711-723.

[48] Oceandy D, Buch MH, Cartwright EJ, Neyses L. The emergence of plasma membrane calcium pump as a novel therapeutic target for heart disease. Mini-Rev. Med. Chem. 2006, 6: 583-588.

[49] Dong Xet al. . Hydroxyapatite nanoparticles induced calcium overload-initiated cancer cell-specific apoptosis through inhibition of PMCA and activation of calpain. J. Mat. Chem. B.. 2023, 11: 7609-7622.

[50] Lubin M. Intracellular potassium and macromolecular synthesis in mammalian cells. Nature. 1967, 213: 451-453.

[51] Fedosova NU, Habeck M, Nissen P. Structure and Function of Na,K-ATPase-the sodium-potassium pump. Compr. Physiol.. 2021, 12: 2659-2679.

[52] Baron R, Neff L, Roy C, Boisvert A, Caplan M. Evidence for a high and specific concentration of (Na⁺,K⁺)ATPase in the plasma membrane of the osteoclast. Cell. 1986, 46: 311-320.

[53] Xiong Set al. . Immunization with Na⁺/K⁺ ATPase DR peptide prevents bone loss in an ovariectomized rat osteoporosis model. Biochem. Pharmacol.. 2018, 156: 281-290.

[54] Song, L., Li, X., Sun, Q. & Zhao, Y. Fxyd5 activates the NF‑kappaB pathway and is involved in chondrocytes inflammation and extracellular matrix degradation. Mol. Med. Rep. 25, 134 (2022).

[55] de Tezanos Pinto F, Adamo HP. The strategic function of the P5-ATPase ATP13A2 in toxic waste disposal. Neurochem. Int.. 2018, 112: 108-113.

[56] Chen P, Bornhorst J, Aschner M. Manganese metabolism in humans. Front. Biosci.. 2018, 23: 1655-1679.

[57] Wells EMet al. . In vivo measurement of bone manganese and association with manual dexterity: a pilot study. Environ. Res.. 2018, 160: 35-38.

[58] Bae Y, Kim M. Manganese supplementation improves mineral density of the spine and femur and serum osteocalcin in rats. Biol. Trace Elem. Res.. 2008, 124: 28-34.

[59] Luthen Fet al. . Influence of manganese ions on cellular behavior of human osteoblasts in vitro. Biomol. Eng.. 2007, 24: 531-536.

[60] Barrioni BRet al. . Osteogenic potential of sol-gel bioactive glasses containing manganese. J. Mater. Sci.-Mater. Med.. 2019, 30: 86.

[61] Fujishiro H, Kambe T. Manganese transport in mammals by zinc transporter family proteins, ZNT and ZIP. J. Pharmacol. Sci.. 2022, 148125-133.

[62] Zhang Ret al. . The endoplasmic reticulum ATP13A1 is essential for MAVS-mediated antiviral innate immunity. Adv. Sci.. 2022, 9. e2203831

[63] Kulicke CAet al. . The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation. J. Biol. Chem.. 2022, 298: 101542.

[64] Rentschler Get al. . ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese. Neurotoxicology. 2012, 33697-702.

[65] Tan Jet al. . Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein. J. Biol. Chem.. 2011, 286: 29654-29662.

[66] Daniel Get al. . alpha-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson’s disease occurs independent of ATP13A2 (PARK9). Neurobiol. Dis.. 2015, 73: 229-243.

[67] Sakai Het al. . Increases in intracellular pH facilitate endocytosis and decrease availability of voltage-gated proton channels in osteoclasts and microglia. J. Physiol.. 2013, 591: 5851-5866.

[68] Mori Het al. . Regulatory mechanisms and physiological relevance of a voltage-gated H⁺ channel in murine osteoclasts: phorbol myristate acetate induces cell acidosis and the channel activation. J. Bone. Miner. Res.. 2003, 18: 2069-2076.

[69] Mori H, Sakai H, Morihata H, Yamano T, Kuno M. A voltage-gated H⁺ channel is a powerful mechanism for pH homeostasis in murine osteoclasts. Kobe J. Med. Sci. 2002, 48: 87-96

[70] Bernheim Let al. . A voltage-dependent proton current in cultured human skeletal muscle myotubes. J. Physiol.. 1993, 470: 313-333.

[71] Li SJ, Zhao Q, Zhou Q, Zhai Y. Expression, purification, crystallization and preliminary crystallographic study of the carboxyl-terminal domain of the human voltage-gated proton channel Hv1. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 2009, 65: 279-281.

[72] Capasso M, DeCoursey TE, Dyer MJS. pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1. Trends Cell Biol.. 2011, 21: 20-28.

[73] Asuaje Aet al. . The inhibition of voltage-gated H⁺ channel (HVCN1) induces acidification of leukemic Jurkat T cells promoting cell death by apoptosis. Pflugers Arch.. 2017, 469: 251-261.

[74] Carafoli E, Krebs J. Why calcium? How calcium became the best communicator. J. Biol. Chem.. 2016, 291: 20849-20857.

[75] Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell Biol.. 2000, 1: 11-21.

[76] Okada, H., Okabe, K. & Tanaka, S. Finely-tuned calcium oscillations in osteoclast differentiation and bone resorption. Int. J. Mol. Sci. 22, 180 (2020).

[77] Catterall WA. Voltage-gated calcium channels. Cold Spring Harbor Perspect. Biol.. 2011, 3: a3947.

[78] Bennett BD, Alvarez U, Hruska KA. Receptor-operated osteoclast calcium sensing. Endocrinology. 2001, 1421968-1974.

[79] Miyauchi Aet al. . Osteoclast cytosolic calcium, regulated by voltage-gated calcium channels and extracellular calcium, controls podosome assembly and bone resorption. J. Cell. Biol.. 1990, 111: 2543-2552.

[80] Noh ALSM, Park H, Zheng T, Ha H, Yim M. L-type Ca²⁺ channel agonist inhibits RANKL-induced osteoclast formation via NFATc1 down-regulation. Life Sci.. 2011, 89: 159-164.

[81] Fan Pet al. . Cav1.3 is upregulated in osteoporosis rat model and promotes osteoclast differentiation from preosteoclast cell line RAW264. J. Cell. Physiol.. 2019, 234: 12821-12827.

[82] Li Bet al. . Ionomycin ameliorates hypophosphatasia via rescuing alkaline phosphatase deficiency-mediated L-type Ca²⁺ channel internalization in mesenchymal stem cells. Bone Res.. 2020, 8: 19.

[83] Datta HK, MacIntyre I, Zaidi M. Intracellular calcium in the control of osteoclast function. I. Voltage-insensitivity and lack of effects of nifedipine, BAYK8644 and diltiazem. Biochem. Biophys. Res. Commun.. 1990, 167183-188.

[84] Striggow F, Ehrlich BE. Ligand-gated calcium channels inside and out. Curr. Opin. Cell. Biol.. 1996, 8: 490-495.

[85] Rahman Tet al. . Two-pore channels provide insight into the evolution of voltage-gated Ca²⁺ and Na⁺ channels. Sci. Signal.. 2014, 7: ra109.

[86] Berridge MJ. Capacitative calcium entry. Biochem. J.. 1995, 3121-11. Pt 1

[87] Inoue R. TRP channels as a newly emerging non-voltage-gated Ca²⁺ entry channel superfamily. Curr. Pharm. Des.. 2005, 11: 1899-1914.

[88] Lee HC, Aarhus R. A derivative of NADP mobilizes calcium stores insensitive to inositol trisphosphate and cyclic ADP-ribose. J. Biol. Chem.. 1995, 270: 2152-2157.

[89] Calcraft PJet al. . NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature. 2009, 459: 596-600.

[90] Woll KA, Van Petegem F. Calcium-release channels: structure and function of IP(3) receptors and ryanodine receptors. Physiol. Rev.. 2022, 102: 209-268.

[91] Morikawa K, Goto T, Tanimura A, Kobayashi S, Maki K. Distribution of inositol 1,4,5-trisphosphate receptors in rat osteoclasts. Acta Histochem. Cytochem.. 2008, 41: 7-13.

[92] Yaroslavskiy BB, Turkova I, Wang Y, Robinson LJ, Blair HC. Functional osteoclast attachment requires inositol-1,4,5-trisphosphate receptor-associated cGMP-dependent kinase substrate. Lab. Investig.. 2010, 90: 1533-1542.

[93] Moonga BSet al. . Ca²⁺ influx through the osteoclastic plasma membrane ryanodine receptor. Am. J. Physiol.-Renal Physiol.. 2002, 282: F921-F932.

[94] Ruas Met al. . TPC1 has two variant isoforms, and their removal has different effects on endo-lysosomal functions compared to loss of TPC2. Mol. Cell. Biol.. 2014, 34: 3981-3992.

[95] Wang Xet al. . TPC proteins are phosphoinositide-activated sodium-selective ion channels in endosomes and lysosomes. Cell. 2012, 151: 372-383.

[96] Notomi Tet al. . Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions. J. Biol. Chem.. 2017, 292: 20998-21010.

[97] Jha A, Ahuja M, Patel S, Brailoiu E, Muallem S. Convergent regulation of the lysosomal two-pore channel-2 by Mg²⁺, NAADP, PI(3,5)P(2) and multiple protein kinases. EMBO J.. 2014, 33: 501-511.

[98] Prakriya Met al. . Orai1 is an essential pore subunit of the CRAC channel. Nature. 2006, 443: 230-233.

[99] Hewavitharana T, Deng X, Soboloff J, Gill DL. Role of STIM and Orai proteins in the store-operated calcium signaling pathway. Cell Calcium. 2007, 42: 173-182.

[100] Zhou Yet al. . The STIM-Orai coupling interface and gating of the Orai1 channel. Cell Calcium. 2017, 63: 8-13.

[101] Robinson LJet al. . Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development. Lab. Invest.. 2012, 92: 1071-1083.

[102] Hwang Set al. . Deletion of Orai1 alters expression of multiple genes during osteoclast and osteoblast maturation. Cell Calcium. 2012, 52: 488-500.

[103] Hwang S, Putney JW. Orai1-mediated calcium entry plays a critical role in osteoclast differentiation and function by regulating activation of the transcription factor NFATc1. FASEB J.. 2012, 26: 1484-1492.

[104] Rychkov GYet al. . Orai1- and Orai2-, but not Orai3-mediated I(CRAC) is regulated by intracellular pH. J. Physiol.. 2022, 600: 623-643.

[105] Inayama Met al. . Orai1-Orai2 complex is involved in store-operated calcium entry in chondrocyte cell lines. Cell Calcium. 2015, 57: 337-347.

[106] Li H. TRP channel classification. Adv. Exp. Med. Biol.. 2017, 976: 1-8.

[107] Ong Eet al. . A TRPC1 protein-dependent pathway regulates osteoclast formation and function. J. Biol. Chem.. 2013, 288: 22219-22232.

[108] Zhu Pet al. . TRPA1 aggravates osteoclastogenesis and osteoporosis through activating endoplasmic reticulum stress mediated by SRXN1. Cell Death Dis.. 2024, 15. 624

[109] Wen Wet al. . Expression and distribution of three transient receptor potential vanilloid(TRPV) channel proteins in human odontoblast-like cells. J. Mol. Histol.. 2017, 48: 367-377.

[110] Nishimura Het al. . Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice. Bone Rep.. 2020, 12: 100268.

[111] He Let al. . TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation. Sci. Rep.. 2017, 7. 42385

[112] Kajiya Het al. . RANKL-induced TRPV2 expression regulates osteoclastogenesis via calcium oscillations. Cell Calcium. 2010, 48260-269.

[113] Klein Set al. . Modulation of transient receptor potential channels 3 and 6 regulates osteoclast function with impact on trabecular bone loss. Calcif. Tissue Int.. 2020, 106: 655-664.

[114] Jin Set al. . Mechanical force modulates periodontal ligament stem cell characteristics during bone remodelling via TRPV4. Cell Prolif.. 2020, 53. e12912

[115] Pozo Aet al. . Cyclic adenosine monophosphate-dependent activation of transient receptor potential vanilloid 4 (TRPV4) channels in osteoblast-like MG-63 cells. Cell. Signal.. 2020, 66: 109486.

[116] Weber K, Erben RG, Rump A, Adamski J. Gene structure and regulation of the murine epithelial calcium channels ECaC1 and 2. Biochem. Biophys. Res. Commun.. 2001, 2891287-1294.

[117] Li SHet al. . TRPV5 and TRPV6 are expressed in placenta and bone tissues during pregnancy in mice. Biotech. Histochem.. 2019, 94: 244-251.

[118] van der Eerden BCJet al. . The epithelial Ca²⁺ channel TRPV5 is essential for proper osteoclastic bone resorption. Proc. Natl. Acad. Sci. USA. 2005, 102: 17507-17512.

[119] Luo Zet al. . Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis. J. Transl. Med.. 2023, 21. 327

[120] Yelshanskaya MV, Nadezhdin KD, Kurnikova MG, Sobolevsky AI. Structure and function of the calcium-selective TRP channel TRPV6. J. Physiol.. 2021, 599: 2673-2697.

[121] Chen F, Ni B, Yang YO, Ye T, Chen A. Knockout of TRPV6 causes osteopenia in mice by increasing osteoclastic differentiation and activity. Cell Physiol. Biochem.. 2014, 33: 796-809.

[122] Cho C, Lee Y, Kim E, Hwang EM, Park J. Physiological functions of the TRPM4 channels via protein interactions. BMB Rep.. 2015, 48: 1-5.

[123] Abed E, Moreau R. Importance of melastatin-like transient receptor potential 7 and magnesium in the stimulation of osteoblast proliferation and migration by platelet-derived growth factor. Am. J. Physiol. Cell Physiol.. 2009, 297: C360-C368.

[124] Shin Met al. . Mesenchymal cell TRPM7 expression is required for bone formation via the regulation of chondrogenesis. Bone. 2023, 166: 116579.

[125] Treusch Set al. . Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis. Proc. Natl. Acad. Sci. USA. 2004, 1014483-4488.

[126] Miedel MTet al. . Membrane traffic and turnover in TRP-ML1-deficient cells: a revised model for mucolipidosis type IV pathogenesis. J. Exp. Med.. 2008, 205: 1477-1490.

[127] Park H, Gholam-Zadeh M, Suh J, Choi H. Lycorine Attenuates Autophagy in Osteoclasts via an Axis of mROS/TRPML1/TFEB to Reduce LPS-Induced Bone Loss. Oxidative Med. Cell. Longev.. 2019, 2019: 8982147.

[128] Erkhembaatar Met al. . Lysosomal Ca²⁺ signaling is essential for osteoclastogenesis and bone remodeling. J. Bone Miner. Res.. 2017, 32385-396.

[129] Yamamoto T. The molecular mechanisms of mitochondrial calcium uptake by calcium uniporter. Yakugaku. Zasshi.. 2021, 141: 491-499.

[130] Williams GSB, Boyman L, Chikando AC, Khairallah RJ, Lederer WJ. Mitochondrial calcium uptake. Proc. Natl. Acad. Sci. USA. 2013, 110: 10479-10486.

[131] Hu W, Yu Y, Sun Y, Yuan F, Zhao F. MiR-25 overexpression inhibits titanium particle-induced osteoclast differentiation via down-regulation of mitochondrial calcium uniporter in vitro. J. Orthop. Surg. Res.. 2022, 17: 133.

[132] Ward KM, Wareham AC. Changes in membrane potential and potassium and sodium activities during postnatal development of mouse skeletal muscle. Exp. Neurol.. 1985, 89554-568.

[133] Kang Het al. . Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease. Cell Rep. 2014, 8: 1210-1224.

[134] Yeon Jet al. . KCNK1 inhibits osteoclastogenesis by blocking the Ca2+ oscillation and JNK-NFATc1 signaling axis. J. Cell Sci.. 2015, 128: 3411-3419

[135] Valverde P, Kawai T, Taubman MA. Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. J. Bone. Miner. Res.. 2004, 19: 155-164.

[136] Gonzalez Cet al. . K⁺ channels: function-structural overview. Compr. Physiol.. 2012, 2: 2087-2149.

[137] Dudem S, Sergeant GP, Thornbury KD, Hollywood MA. Calcium-activated K⁺ channels (K(Ca)) and therapeutic implications. Handb Exp Pharmacol. 2021, 267: 379-416.

[138] Wilson HA, Chused TM. Lymphocyte membrane potential and Ca²⁺-sensitive potassium channels described by oxonol dye fluorescence measurements. J. Cell. Physiol.. 1985, 125: 72-81.

[139] Brenner R, Jegla TJ, Wickenden A, Liu Y, Aldrich RW. Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4. J. Biol. Chem.. 2000, 275: 6453-6461.

[140] Ghatta S, Nimmagadda D, Xu X, O’Rourke ST. Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol. Ther.. 2006, 110: 103-116.

[141] Weatherall KL, Goodchild SJ, Jane DE, Marrion NV. Small conductance calcium-activated potassium channels: from structure to function. Prog. Neurobiol.. 2010, 91: 242-255.

[142] Jensen BSet al. . Characterization of the cloned human intermediate-conductance Ca²⁺-activated K⁺ channel. Am J Physiol.. 1998, 275: C848-C856.

[143] Wu S, Huang Y, Liao Y. Effects of ibandronate sodium, a nitrogen-containing bisphosphonate, on intermediate-conductance calcium-activated potassium channels in osteoclast precursor cells (RAW 264.7). J. Membr. Biol.. 2015, 248: 103-115.

[144] Latorre R, Brauchi S. Large conductance Ca²⁺-activated K⁺ (BK) channel: activation by Ca²⁺ and voltage. Biol. Res.. 2006, 39: 385-401.

[145] Jiang Let al. . Activation of BK channels prevents diabetes-induced osteopenia by regulating mitochondrial Ca²⁺ and SLC25A5/ANT2-PINK1-PRKN-mediated mitophagy. Autophagy. 2024, 20: 2388-2404.

[146] Quayle JM, Nelson MT, Standen NB. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol. Rev.. 1997, 77: 1165-1232.

[147] Kubo Y, Baldwin TJ, Jan YN, Jan LY. Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature. 1993, 362: 127-133.

[148] Hibino Het al. . Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol. Rev.. 2010, 90: 291-366.

[149] Kelly ME, Dixon SJ, Sims SM. Inwardly rectifying potassium current in rabbit osteoclasts: a whole-cell and single-channel study. J. Membr. Biol.. 1992, 126: 171-181.

[150] Kamuene JM, Xu Y, Plant LD. The pharmacology of two-pore domain potassium channels. Handb. Exp. Pharmacol.. 2021, 267: 417-443.

[151] Feliciangeli S, Chatelain FC, Bichet D, Lesage F. The family of K2P channels: salient structural and functional properties. J. Physiol.. 2015, 593: 2587-2603.

[152] Feinshreiber L, Singer-Lahat D, Ashery U, Lotan I. Voltage-gated potassium channel as a facilitator of exocytosis. Ann. N.Y. Acad. Sci.. 2009, 1152: 87-92.

[153] Gulbis JM, Mann S, MacKinnon R. Structure of a voltage-dependent K⁺ channel beta subunit. Cell. 1999, 97: 943-952.

[154] McCormack Ket al. . Genetic analysis of the mammalian K⁺ channel beta subunit Kvbeta 2 (Kcnab2). J. Biol. Chem.. 2002, 277: 13219-13228.

[155] Yan Let al. . Fe2O3 nanoparticles suppress Kv1.3 channels via affecting the redox activity of Kvbeta2 subunit in Jurkat T cells. Nanotechnology. 2015, 26: 505103.

[156] Tu Het al. . Hyperpolarization-activated, cyclic nucleotide-gated cation channels: roles in the differential electrophysiological properties of rat primary afferent neurons. J. Neurosci. Res.. 2004, 76713-722.

[157] Wilson CM, Stecyk JAW, Couturier CS, Nilsson GE, Farrell AP. Phylogeny and effects of anoxia on hyperpolarization-activated cyclic nucleotide-gated channel gene expression in the heart of a primitive chordate, the Pacific hagfish (Eptatretus stoutii). J. Exp. Biol.. 2013, 216: 4462-4472

[158] Herrmann S, Schnorr S, Ludwig A. HCN channels-modulators of cardiac and neuronal excitability. Int. J. Mol. Sci.. 2015, 16: 1429-1447.

[159] Notomi Tet al. . Zinc-induced effects on osteoclastogenesis involves activation of hyperpolarization-activated cyclic nucleotide modulated channels via changes in membrane potential. J. Bone. Miner. Res.. 2015, 30: 1618-1626.

[160] Hiraoka M. Metabolic pathways for ion homeostasis and persistent Na⁺ current. J. Cardiovasc. Electrophysiol.. 2006, 17: S124-S126.

[161] Byers MR, Rafie MM, Westenbroek RE. Dexamethasone effects on Na(v)1.6 in tooth pulp, dental nerves, and alveolar osteoclasts of adult rats. Cell. Tissue. Res.. 2009, 338: 217-226.

[162] Rolvien Tet al. . Severe bone loss and multiple fractures in SCN8A-related epileptic encephalopathy. Bone. 2017, 103: 136-143.

[163] Hu Set al. . Role of epithelial sodium channel in rat osteoclast differentiation and bone resorption. Nan Fang Yi Ke Da Xue Xue Bao. 2016, 36: 1148-1152

[164] Dohke Tet al. . Regional osteoporosis due to osteoclast activation as a trigger for the pain-like behaviors in tail-suspended mice. J. Orthop. Res.. 2017, 35: 1226-1236.

[165] Catarsi S, Babinski K, Seguela P. Selective modulation of heteromeric ASIC proton-gated channels by neuropeptide FF. Neuropharmacology. 2001, 41: 592-600.

[166] Li Xet al. . Acid-sensing ion channel 1a is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1. FEBS Lett.. 2013, 587: 3236-3242.

[167] Li X, Ye J, Xu M, Zhao M, Yuan F. Evidence that activation of ASIC1a by acidosis increases osteoclast migration and adhesion by modulating integrin/Pyk2/Src signaling pathway. Osteoporos. Int.. 2017, 28: 2221-2231.

[168] Baltaci AK, Yuce K. Zinc transporter proteins. Neurochem. Res.. 2018, 43: 517-530.

[169] McCall KA, Huang C, Fierke CA. Function and mechanism of zinc metalloenzymes. J. Nutr.. 2000, 130: 1437S-1446S.

[170] Astudillo C, Fernandez AC, Blair MW, Cichy KA. The Phaseolus vulgaris ZIP gene family: identification, characterization, mapping, and gene expression. Front. Plant Sci.. 2013, 4: 286.

[171] Dufner-Beattie J, Huang ZL, Geiser J, Xu W, Andrews GK. Mouse ZIP1 and ZIP3 genes together are essential for adaptation to dietary zinc deficiency during pregnancy. Genesis. 2006, 44239-251.

[172] Franklin RBet al. . Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells. J. Inorg. Biochem.. 2003, 96: 435-442.

[173] Eide DJ. The SLC39 family of metal ion transporters. Pflugers Arch.. 2004, 447: 796-800.

[174] Schweigel-Rontgen M. The families of zinc (SLC30 and SLC39) and copper (SLC31) transporters. Curr. Top. Membr.. 2014, 73: 321-355.

[175] Khadeer MA, Sahu SN, Bai G, Abdulla S, Gupta A. Expression of the zinc transporter ZIP1 in osteoclasts. Bone. 2005, 37: 296-304.

[176] Shang, J. et al. Role of Zip1 in the regulation of NPY expression by MLT to promote fracture healing in rats. Eur. J. Histochem. 64, 3183 (2020).

[177] Wang Fet al. . Zinc-stimulated endocytosis controls activity of the mouse ZIP1 and ZIP3 zinc uptake transporters. J. Biol. Chem.. 2004, 279: 24631-24639.

[178] Kagara N, Tanaka N, Noguchi S, Hirano T. Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells. Cancer Sci. 2007, 98: 692-697.

[179] Kelleher SLet al. . Mapping the zinc-transporting system in mammary cells: molecular analysis reveals a phenotype-dependent zinc-transporting network during lactation. J. Cell. Physiol.. 2012, 227: 1761-1770.

[180] Chowanadisai W. Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development. PloS One. 2014, 9: e111535.

[181] Bin Bet al. . Biochemical characterization of human ZIP13 protein: a homo-dimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers-Danlos syndrome. J. Biol. Chem.. 2011, 28640255-40265.

[182] Fukada Tet al. . The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways. PloS One. 2008, 3. e3642

[183] Thambiayya K, Kaynar AM, St Croix CM, Pitt BR. Functional role of intracellular labile zinc in pulmonary endothelium. Pulm. Circ.. 2012, 2: 443-451.

[184] Hara Tet al. . Physiological roles of zinc transporters: molecular and genetic importance in zinc homeostasis. J. Physiol. Sci.. 2017, 67: 283-301.

[185] Inoue Ket al. . Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5. Hum. Mol. Genet.. 2002, 11: 1775-1784.

[186] Lyubartseva G, Smith JL, Markesbery WR, Lovell MA. Alterations of zinc transporter proteins ZnT-1, ZnT-4 and ZnT-6 in preclinical Alzheimer’s disease brain. Brain. Pathol.. 2010, 20: 343-350.

[187] Prakash A, Bharti K, Majeed ABA. Zinc: indications in brain disorders. Fundam. Clin. Pharmacol.. 2015, 29: 131-149.

[188] Zhang Xet al. . Zinc transporter 5 and zinc transporter 7 induced by high glucose protects peritoneal mesothelial cells from undergoing apoptosis. Cell. Signal.. 2013, 25: 999-1010.

[189] Romani AMP. Cellular magnesium homeostasis. Arch. Biochem. Biophys.. 2011, 512: 1-23.

[190] Romani A. Regulation of magnesium homeostasis and transport in mammalian cells. Arch. Biochem. Biophys.. 2007, 458: 90-102.

[191] Lopez Martinez J, Sanchez Castilla M, Garcia De Lorenzo Y, Mateos A, Culebras Fernandez JM. Magnesium: metabolism and requirements. Nutr. Hosp.. 1997, 12: 4-14

[192] Rubin H. The membrane, magnesium, mitosis (MMM) model of cell proliferation control. Magnes. Res.. 2005, 18: 268-274

[193] Jensen PE, Gibson LC, Hunter CN. ATPase activity associated with the magnesium-protoporphyrin IX chelatase enzyme of Synechocystis PCC6803: evidence for ATP hydrolysis during Mg²⁺ insertion, and the MgATP-dependent interaction of the ChlI and ChlD subunits. Biochem. J.. 1999, 339: 127-134. Pt 1

[194] Garfinkel L, Garfinkel D. Magnesium regulation of the glycolytic pathway and the enzymes involved. Magnesium. 1985, 4: 60-72

[195] Leidi M, Dellera F, Mariotti M, Maier JAM. High magnesium inhibits human osteoblast differentiation in vitro. Magnes. Res.. 2011, 24: 1-6

[196] Castiglioni S, Cazzaniga A, Albisetti W, Maier JAM. Magnesium and osteoporosis: current state of knowledge and future research directions. Nutrients. 2013, 5: 3022-3033.

[197] Qiao Wet al. . TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration. Nat. Commun.. 2021, 12. 2885

[198] Astor MCet al. . Hypomagnesemia and functional hypoparathyroidism due to novel mutations in the Mg-channel TRPM6. Endocr. Connect.. 2015, 4: 215-222.

[199] Risco F, Traba ML. Bone-specific binding sites for 1,25(OH)2D3 in magnesium deficiency. J. Physiol. Biochem.. 2004, 60: 199-203.

[200] Wolf FI, Trapani V. MagT1: a highly specific magnesium channel with important roles beyond cellular magnesium homeostasis. Magnes. Res.. 2011, 24: S86-S91.

[201] Castiglioni S, Romeo V, Locatelli L, Cazzaniga A, Maier JAM. TRPM7 and MagT1 in the osteogenic differentiation of human mesenchymal stem cells in vitro. Sci. Rep.. 2018, 8. 16195

[202] Gregan J, Kolisek M, Schweyen RJ. Mitochondrial Mg²⁺ homeostasis is critical for group II intron splicing in vivo. Genes. Dev.. 2001, 15: 2229-2237.

[203] Cabezas-Bratesco Det al. . The different roles of the channel-kinases TRPM6 and TRPM7. Curr. Med. Chem.. 2015, 22: 2943-2953.

[204] Yu Net al. . SLC41A1 knockdown inhibits angiotensin II-induced cardiac fibrosis by preventing Mg²⁺ efflux and Ca²⁺ signaling in cardiac fibroblasts. Arch. Biochem. Biophys.. 2014, 564: 74-82.

[205] de Baaij JHFet al. . Identification of SLC41A3 as a novel player in magnesium homeostasis. Sci. Rep.. 2016, 6. 28565

[206] Klimaczewski CVet al. . Peumus boldus attenuates copper-induced toxicity in Drosophila melanogaster. Biomed. Pharmacother.. 2018, 97: 1-8.

[207] Li D, Gao Z, Li Q, Liu X, Liu H. Cuproptosis-a potential target for the treatment of osteoporosis. Front. Endocrinol.. 2023, 14: 1135181.

[208] Xu Xet al. . Copper-modified Ti6Al4 V suppresses inflammatory response and osteoclastogenesis while enhancing extracellular matrix formation for osteoporotic bone regeneration. ACS Biomater. Sci. Eng.. 2018, 43364-3373.

[209] Ohrvik H, Thiele DJ. How copper traverses cellular membranes through the mammalian copper transporter 1, Ctr1. Ann. N.Y. Acad. Sci.. 2014, 1314: 32-41.

[210] Leary SC, Ralle M. Advances in visualization of copper in mammalian systems using X-ray fluorescence microscopy. Curr. Opin. Chem. Biol.. 2020, 55: 19-25.

[211] Lutsenko, S. Dynamic and cell-specific transport networks for intracellular copper ions. J. Cell Sci. 134, jcs240523 (2021).

[212] Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin. Hematol.. 1998, 35: 35-54

[213] Knutson MD. Non-transferrin-bound iron transporters. Free. Radic. Biol. Med.. 2019, 133: 101-111.

[214] Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of mammalian iron metabolism. Cell. 2010, 142: 24-38.

[215] Balogh, E., Paragh, G. & Jeney, V. Influence of iron on bone homeostasis. Pharmaceuticals.11, 107 (2018).

[216] Dong Yet al. . A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis. Cell Metab. 2024, 36: 1679-1695.

[217] Donovan Aet al. . Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000, 403: 776-781.

[218] Xie W, Lorenz S, Dolder S, Hofstetter W. Extracellular iron is a modulator of the differentiation of osteoclast lineage cells. Calcif. Tissue Int.. 2016, 98: 275-283.

[219] Lin Fet al. . Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury. Cell Death Dis. 2022, 13. 271

[220] Sun F, Zhou JL, Liu ZL, Jiang ZW, Peng H. Dexamethasone induces ferroptosis via P53/SLC7A11/GPX4 pathway in glucocorticoid-induced osteonecrosis of the femoral head. Biochem. Biophys. Res. Commun.. 2022, 602: 149-155.

[221] Yang Yet al. . Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis. Bone Res.. 2022, 10: 26.

[222] Ge, W. et al. Advanced glycation end products promote osteoporosis by inducing ferroptosis in osteoblasts. Mol. Med. Rep. 25, 140 (2022).

[223] Ma Het al. . Melatonin suppresses ferroptosis induced by high glucose via activation of the Nrf2/HO-1 signaling pathway in type 2 diabetic osteoporosis. Oxidative Med. Cell. Longev.. 2020, 20209067610.

[224] Wang Xet al. . Mitochondrial ferritin deficiency promotes osteoblastic ferroptosis via mitophagy in type 2 diabetic osteoporosis. Biol. Trace Elem. Res.. 2022, 200298-307.

[225] Qu X, Sun Z, Wang Y, Ong HS. Zoledronic acid promotes osteoclasts ferroptosis by inhibiting FBXO9-mediated p53 ubiquitination and degradation. Peerj. 2021, 9: e12510.

[226] Ni Set al. . Hypoxia inhibits RANKL-induced ferritinophagy and protects osteoclasts from ferroptosis. Free. Radic. Biol. Med.. 2021, 169271-282.

[227] Coste Bet al. . Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010, 330: 55-60.

[228] Wang Let al. . Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat. Commun.. 2020, 11. 282

[229] Hendrickx Get al. . Piezo1 inactivation in chondrocytes impairs trabecular bone formation. J. Bone. Miner. Res.. 2021, 36: 369-384.

[230] Bratengeier C, Liszka A, Hoffman J, Bakker AD, Fahlgren A. High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cells. FASEB J.. 2020, 34: 3755-3772.

[231] Shindo, S. et al. Piezo1 protects against inflammatory bone loss via a unique Ca(2+)-independent mechanism in osteoclasts. Front. Immunol.16, 1661538 (2025).

[232] Guan Het al. . Magnetic aggregation-induced bone-targeting nanocarrier with effects of Piezo1 activation and osteogenic-angiogenic coupling for osteoporotic bone repair. Adv. Mater.. 2024, 36. e2312081

[233] Cai Get al. . Piezo1-mediated M2 macrophage mechanotransduction enhances bone formation through secretion and activation of transforming growth factor-beta1. Cell Prolif.. 2023, 56. e13440

[234] Wang, S. et al. Nociceptor neurons facilitate orthodontic tooth movement via Piezo2 in mice. J. Dent. Res. 104, 890-899 (2025).

[235] Wyllie DJA, Bowie D. Ionotropic glutamate receptors: structure, function and dysfunction. J. Physiol.. 2022, 600: 175-179.

[236] Kelly JB, Zhang H. Contribution of AMPA and NMDA receptors to excitatory responses in the inferior colliculus. Hear. Res.. 2002, 168: 35-42.

[237] Merle B, Itzstein C, Delmas PD, Chenu C. NMDA glutamate receptors are expressed by osteoclast precursors and involved in the regulation of osteoclastogenesis. J. Cell. Biochem.. 2003, 90: 424-436.

[238] Kiyohara Set al. . Effects of N-methyl-d-aspartate receptor antagonist MK-801 (dizocilpine) on bone homeostasis in mice. J. Oral Biosci.. 2020, 62: 131-138.

[239] Baek JM, Kim J, Yoon K, Oh J, Lee MS. Ebselen is a potential anti-osteoporosis agent by suppressing receptor activator of nuclear factor kappa-B ligand-induced osteoclast differentiation in vitro and lipopolysaccharide-induced inflammatory bone destruction in vivo. Int. J. Biol. Sci.. 2016, 12: 478-488.

[240] Coddou C, Yan Z, Obsil T, Huidobro-Toro JP, Stojilkovic SS. Activation and regulation of purinergic P2X receptor channels. Pharmacol. Rev.. 2011, 63: 641-683.

[241] Schmid R, Evans RJ. ATP-gated P2X receptor channels: molecular insights into functional roles. Annu. Rev. Physiol.. 2019, 81: 43-62.

[242] Barbosa CMVet al. . Differentiation of hematopoietic stem cell and myeloid populations by ATP is modulated by cytokines. Cell Death Dis.. 2011, 2. e165

[243] Naemsch LN, Weidema AF, Sims SM, Underhill TM, Dixon SJ. P2X(4) purinoceptors mediate an ATP-activated, non-selective cation current in rabbit osteoclasts. J. Cell Sci.. 1999, 112: 4425-4435. Pt 23

[244] Kim Het al. . The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts. Sci. Rep.. 2017, 7. 196

[245] Kim Het al. . The purinergic receptor P2X5 contributes to bone loss in experimental periodontitis. BMB Rep.. 2018, 51: 468-473.

[246] Agrawal A, Jorgensen NR. Extracellular purines and bone homeostasis. Biochem. Pharmacol.. 2021, 187: 114425.

[247] Morrison MS, Turin L, King BF, Burnstock G, Arnett TR. ATP is a potent stimulator of the activation and formation of rodent osteoclasts. J. Physiol.. 1998, 511495-500. Pt 2

[248] Surprenant A, Rassendren F, Kawashima E, North RA, Buell G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science. 1996, 272: 735-738.

[249] Brandao-Burch A, Key ML, Patel JJ, Arnett TR, Orriss IR. The P2X7 receptor is an important regulator of extracellular ATP levels. Front. Endocrinol.. 2012, 3: 41.

[250] Lu Jet al. . New mechanistic understanding of osteoclast differentiation and bone resorption mediated by P2X7 receptors and PI3K-Akt-GSK3beta signaling. Cell. Mol. Biol. Lett.. 2024, 29100.

[251] Agrawal Aet al. . The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro. Purinergic Signal. 2010, 6307-315.

[252] Gartland A, Buckley KA, Bowler WB, Gallagher JA. Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro. Calcif. Tissue Int.. 2003, 73: 361-369.

[253] Armstrong S, Pereverzev A, Dixon SJ, Sims SM. Activation of P2X7 receptors causes isoform-specific translocation of protein kinase C in osteoclasts. J. Cell Sci.. 2009, 122: 136-144.

[254] Korcok J, Raimundo LN, Ke HZ, Sims SM, Dixon SJ. Extracellular nucleotides act through P2X7 receptors to activate NF-kappaB in osteoclasts. J. Bone. Miner. Res.. 2004, 19: 642-651.

[255] Ma Yet al. . The effect of P2X7R-mediated Ca²⁺ signaling in OPG-induced osteoclasts adhesive structure damage. Exp. Cell Res.. 2019, 383: 111555.

[256] Hiken JF, Steinberg TH. ATP downregulates P2X7 and inhibits osteoclast formation in RAW cells. Am. J. Physiol. Cell Physiol.. 2004, 287C403-C412.

[257] Ma, Y. et al. P2X7 receptor knockdown suppresses osteoclast differentiation by inhibiting autophagy and Ca²⁺/calcineurin signaling. Mol. Med. Rep. 25, 160 (2022).

[258] Braun AP, Schulman H. Distinct voltage-dependent gating behaviours of a swelling-activated chloride current in human epithelial cells. J. Physiol.. 1996, 495: 743-753. Pt 3

[259] Berndt N, Hoffmann S, Benda J, Holzhutter H. The influence of the chloride currents on action potential firing and volume regulation of excitable cells studied by a kinetic model. J. Theor. Biol.. 2011, 276: 42-49.

[260] Gelband CH, Greco PG, Martens JR. Voltage-dependent chloride channels: invertebrates to man. J. Exp. Zool.. 1996, 275: 277-282.

[261] Nilius B, Droogmans G. Amazing chloride channels: an overview. Acta Physiol. Scand.. 2003, 177: 119-147.

[262] Jentsch TJ, Neagoe I, Scheel O. CLC chloride channels and transporters. Curr. Opin. Neurobiol.. 2005, 15: 319-325.

[263] Pangrazio Aet al. . Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum. Mutat.. 2010, 31: E1071-E1080.

[264] Kornak Uet al. . Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. 2001, 104: 205-215.

[265] Piret SEet al. . Autosomal dominant osteopetrosis associated with renal tubular acidosis is due to a CLCN7 mutation. Am. J. Med. Genet. A. 2016, 170: 2988-2992.

[266] Majumdar A, Capetillo-Zarate E, Cruz D, Gouras GK, Maxfield FR. Degradation of Alzheimer’s amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes. Mol. Biol. Cell.. 2011, 22: 1664-1676.

[267] Neutzsky-Wulff AV, Karsdal MA, Henriksen K. Characterization of the bone phenotype in ClC-7-deficient mice. Calcif. Tissue Int.. 2008, 83: 425-437.

[268] Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature. 2006, 440: 220-223.

[269] Di Zanni Eet al. . Pathobiologic mechanisms of neurodegeneration in osteopetrosis derived from structural and functional analysis of 14 ClC-7 mutants. J. Bone. Miner. Res.. 2021, 36: 531-545.

[270] Parenti G, Andria G, Valenzano KJ. Pharmacological chaperone therapy: preclinical development, clinical translation, and prospects for the treatment of lysosomal storage disorders. Mol. Ther.. 2015, 23: 1138-1148.

[271] Wu, J. Z. et al. ClC-7 drives intraphagosomal chloride accumulation to support hydrolase activity and phagosome resolution. J. Cell. Biol. 222, e202208155 (2023).

[272] Iyer, H. & Talbot, W. S. The Cl- transporter ClC-7 is essential for phagocytic clearance by microglia. J. Cell Sci. 137, jcs261616 (2024).

[273] Cai Yet al. . Downregulation of chloride voltage-gated channel 7 contributes to hyperalgesia following spared nerve injury. J. Biol. Chem.. 2024, 300: 107779.

[274] Wang Het al. . ClC-7 Deficiency impairs tooth development and eruption. Sci. Rep.. 2016, 6. 19971

[275] Zhang Yet al. . ClC-7 Regulates the pattern and early development of craniofacial bone and tooth. Theranostics. 2019, 91387-1400.

[276] Ohgi K, Okamoto F, Kajiya H, Sakagami R, Okabe K. Antibodies against ClC7 inhibit extracellular acidification-induced Cl^- currents and bone resorption activity in mouse osteoclasts. Naunyn. Schmiedebergs. Arch. Pharmacol.. 2011, 383: 79-90.

[277] Okamoto Fet al. . Intracellular ClC-3 chloride channels promote bone resorption in vitro through organelle acidification in mouse osteoclasts. Am. J. Physiol. Cell Physiol.. 2008, 294: C693-C701.

[278] Wang Het al. . Chloride channel ClC-3 promotion of osteogenic differentiation through Runx2. J. Cell. Biochem.. 2010, 111: 49-58.

[279] Wang Het al. . ClC-3 chloride channel functions as a mechanically sensitive channel in osteoblasts. Biochem. Cell. Biol.. 2015, 93: 558-565.

[280] Al Khamici Het al. . Members of the chloride intracellular ion channel protein family demonstrate glutaredoxin-like enzymatic activity. PloS One. 2015, 10. e115699

[281] Singh H. Two decades with dimorphic chloride intracellular channels (CLICs). FEBS Lett.. 2010, 584: 2112-2121.

[282] Sun HJet al. . A proteomic analysis during serial subculture and osteogenic differentiation of human mesenchymal stem cell. J. Orthop. Res.. 2006, 24: 2059-2071.

[283] Jiang Let al. . Intracellular chloride channel protein CLIC1 regulates macrophage function through modulation of phagosomal acidification. J. Cell Sci.. 2012, 125: 5479-5488

[284] Schaller Set al. . The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation. J. Bone. Miner. Res.. 2004, 19: 1144-1153.

[285] Proutski I, Karoulias N, Ashley RH. Overexpressed chloride intracellular channel protein CLIC4 (p64H1) is an essential component of novel plasma membrane anion channels. Biochem. Biophys. Res. Commun.. 2002, 297: 317-322.

[286] Singh H, Ashley RH. CLIC4 (p64H1) and its putative transmembrane domain form poorly selective, redox-regulated ion channels. Mol. Membr. Biol.. 2007, 24: 41-52.

[287] Argenzio Eet al. . CLIC4 regulates cell adhesion and beta1 integrin trafficking. J. Cell Sci.. 2014, 127: 5189-5203

[288] Domingo-Fernandez R, Coll RC, Kearney J, Breit S, O’Neill LAJ. The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1beta transcription and activate the NLRP3 inflammasome. J. Biol. Chem.. 2017, 292: 12077-12087.

[289] Abdul-Salam VBet al. . CLIC4/Arf6 pathway. Circ. Res.. 2019, 124: 52-65.

[290] Hartzell HC, Yu K, Xiao Q, Chien L, Qu Z. Anoctamin/TMEM16 family members are Ca²⁺-activated Cl- channels. J. Physiol.. 2009, 587: 2127-2139.

[291] Kamaleddin MA. Molecular, biophysical, and pharmacological properties of calcium-activated chloride channels. J. Cell. Physiol.. 2018, 233: 787-798.

[292] Ehlen HWAet al. . Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues. J. Bone. Miner. Res.. 2013, 28: 246-259.

[293] Oh U, Jung J. Cellular functions of TMEM16/anoctamin. Pflugers Arch.. 2016, 468: 443-453.

[294] Ousingsawat Jet al. . Anoctamin 6 mediates effects essential for innate immunity downstream of P2X7 receptors in macrophages. Nat. Commun.. 2015, 6. 6245

[295] Liu Get al. . Involvement of Ca²⁺ activated Cl- channel Ano6 in platelet activation and apoptosis. Cell Physiol. Biochem.. 2015, 37: 1934-1944.

[296] Shaibani A, Khan S, Shinawi M. Autosomal dominant ANO5-related disorder associated with myopathy and gnathodiaphyseal dysplasia. Neurol. Genet.. 2021, 7: e612.

[297] Liu, X. et al. Ano5 deficiency disturbed bone formation by inducing osteoclast apoptosis in Gnathodiaphyseal dysplasia. Exp. Cell Res. 447, 114493 (2025).

[298] Zhang, S. et al. Anoctamin5 deficiency enhances ATG9A-dependent autophagy, inducing osteogenesis and gnathodiaphyseal dysplasia-like bone formation. JCI Insight.10, e189817 (2025).

[299] Ishihara K, Suzuki J, Nagata S. Role of Ca²⁺ in the stability and function of TMEM16F and 16K. Biochemistry. 2016, 553180-3188.

[300] Jacobsen KSet al. . The role of TMEM16A (ANO1) and TMEM16F (ANO6) in cell migration. Pflugers Arch.. 2013, 465: 1753-1762.

[301] Sirianant L, Ousingsawat J, Wanitchakool P, Schreiber R, Kunzelmann K. Cellular volume regulation by anoctamin 6: Ca²⁺, phospholipase A2 and osmosensing. Pflugers Arch.. 2016, 468: 335-349.

[302] Xuan Z, Wang Y, Xie J. ANO6 promotes cell proliferation and invasion in glioma through regulating the ERK signaling pathway. Oncotargets Ther.. 2019, 12: 6721-6731.

[303] Yang Jet al. . PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel. Science. 2019, 364: 395-399.

[304] Ruan Z, Osei-Owusu J, Du J, Qiu Z, Lu W. Structures and pH-sensing mechanism of the proton-activated chloride channel. Nature. 2020, 588: 350-354.

[305] Osei-Owusu Jet al. . Proton-activated chloride channel PAC regulates endosomal acidification and transferrin receptor-mediated endocytosis. Cell Rep.. 2021, 34: 108683.

[306] Xue, P. et al. Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model. J. Clin. Invest. 134, e168155 (2024).

[307] Pan, D. et al. Senescence of endplate osteoclasts induces sensory innervation and spinal pain. Elife. 12, RP92889 (2024).

[308] Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch.. 2004, 447689-709.

[309] Seifert EL, Ligeti E, Mayr JA, Sondheimer N, Hajnoczky G. The mitochondrial phosphate carrier: role in oxidative metabolism, calcium handling and mitochondrial disease. Biochem. Biophys. Res. Commun.. 2015, 464: 369-375.

[310] Boulet Aet al. . The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis. J. Biol. Chem.. 2018, 293: 1887-1896.

[311] Wei A, Liu T, O’Rourke B. Dual effect of phosphate transport on mitochondrial Ca²⁺ dynamics. J. Biol. Chem.. 2015, 290: 16088-16098.

[312] Junkun Let al. . Curcumin downregulates phosphate carrier and protects against doxorubicin-induced cardiomyocyte apoptosis. Biomed. Res. Int.. 2016, 2016: 1980763.

[313] Kwong JQet al. . Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ.. 2014, 211209-1217.

[314] Wang Pet al. . METTL14-mediated methylation of SLC25A3 mitigates mitochondrial damage in osteoblasts, leading to the improvement of osteoporosis. Exp. Gerontol.. 2024, 194: 112496.

[315] Zhou Tet al. . Single-cell transcriptomics in MI identify Slc25a4 as a new modulator of mitochondrial malfunction and apoptosis-associated cardiomyocyte subcluster. Sci. Rep.. 2024, 14. 9274

[316] Le J, Chen Y, Yang W, Chen L, Ye J. Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus. Acta Pharm. Sin. B.. 2024, 14437-454.

[317] Zhu Set al. . Slc25a5 regulates adipogenesis by modulating ERK signaling in OP9 cells. Cell. Mol. Biol. Lett.. 2022, 27: 11.

[318] Correction to Down-regulated lncRNA SLC25A5-AS1 facilitates cell growth and inhibits apoptosis via miR-19a-3p/PTEN/PI3K/AKT signalling pathway in gastric cancer. J. Cell. Mol. Med. 27, 3215–3216 (2023).

[319] Zhou X, Paredes JA, Krishnan S, Curbo S, Karlsson A. The mitochondrial carrier SLC25A10 regulates cancer cell growth. Oncotarget. 2015, 69271-9283.

[320] Huypens Pet al. . The dicarboxylate carrier plays a role in mitochondrial malate transport and in the regulation of glucose-stimulated insulin secretion from rat pancreatic beta cells. Diabetologia. 2011, 54: 135-145.

[321] Lin Yet al. . The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J. Biol. Chem.. 2005, 280: 4617-4626.

[322] Wang Get al. . SLC25A10 performs an oncogenic role in human osteosarcoma. Oncol. Lett.. 2020, 20: 2

[323] Dong J, Zhong J, Xu Y, Ma Y, Duan X. Research progress on structure, function and disease correlation of solute carrier family 4. Sheng Li Xue Bao. 2023, 75137-150

[324] Choi I. SLC4A transporters. Curr. Top. Membr.. 2012, 70: 77-103.

[325] Cai Let al. . Dietary sodium enhances the expression of SLC4 family transporters, IRBIT, L-IRBIT, and PP1 in rat kidney: Insights into the molecular mechanism for renal sodium handling. Front. Physiol.. 2023, 14: 1154694.

[326] Urso K, Charles JF, Shull GE, Aliprantis AO, Balestrieri B. Anion exchanger 2 regulates dectin-1-dependent phagocytosis and killing of Candida albicans. PloS One. 2016, 11. e158893

[327] Wu J, Glimcher LH, Aliprantis AO. HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function. Proc. Natl. Acad. Sci. USA. 2008, 10516934-16939.

[328] Coury Fet al. . SLC4A2-mediated Cl^-/HCO3^- exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts. Proc. Natl. Acad. Sci. USA. 2013, 110: 2163-2168.

[329] Xue J, Ikegawa S, Guo L. SLC4A2, another gene involved in acid-base balancing machinery of osteoclasts, causes osteopetrosis. Bone. 2023, 167: 116603.

[330] Xue Jet al. . SLC4A2 deficiency causes a new type of osteopetrosis. J. Bone. Miner. Res.. 2022, 37226-235.

[331] Josephsen Ket al. . Targeted disruption of the Cl^-/HCO3^- exchanger Ae2 results in osteopetrosis in mice. Proc. Natl. Acad. Sci. USA. 2009, 106: 1638-1641.

[332] Riihonen R, Nielsen S, Vaananen HK, Laitala-Leinonen T, Kwon T. Degradation of hydroxyapatite in vivo and in vitro requires osteoclastic sodium-bicarbonate co-transporter NBCn1. Matrix Biol.. 2010, 29: 287-294.

[333] Bouyer Pet al. . Colony-stimulating factor-1 increases osteoclast intracellular pH and promotes survival via the electroneutral Na/HCO3 cotransporter NBCn1. Endocrinology. 2007, 148: 831-840.

[334] Ali ESet al. . The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis. Mol. Cell.. 2022, 82: 3284-3298.

[335] Galvan A, Fernandez E. Eukaryotic nitrate and nitrite transporters. Cell. Mol. Life Sci.. 2001, 58: 225-233.

[336] Lundberg JO, Weitzberg E, Cole JA, Benjamin N. Nitrate, bacteria and human health. Nat. Rev. Microbiol.. 2004, 2: 593-602.

[337] Wang Y, Cheng Y, Chen K, Tsay Y. Nitrate transport, signaling, and use efficiency. Annu. Rev. Plant Biol.. 2018, 69: 85-122.

[338] Kalyanaraman Het al. . A novel, direct NO donor regulates osteoblast and osteoclast functions and increases bone mass in ovariectomized mice. J. Bone. Miner. Res.. 2017, 32: 46-59.

[339] Frommer WB, Hummel S, Rentsch D. Cloning of an Arabidopsis histidine transporting protein related to nitrate and peptide transporters. FEBS Lett.. 1994, 347: 185-189.

[340] Quesada Aet al. . PCR-identification of a Nicotiana plumbaginifolia cDNA homologous to the high-affinity nitrate transporters of the crnA family. Plant Mol. Biol.. 1997, 34: 265-274.

[341] Dong SS, Williams JP, Jordan SE, Cornwell T, Blair HC. Nitric oxide regulation of cGMP production in osteoclasts. J. Cell. Biochem.. 1999, 73: 478-487.

[342] Jeddi S, Yousefzadeh N, Kashfi K, Ghasemi A. Role of nitric oxide in type 1 diabetes-induced osteoporosis. Biochem. Pharmacol.. 2022, 197: 114888.

[343] Li X, Augustine A, Chen S, Fliegel L. Stop codon polymorphisms in the human SLC9A1 gene disrupt or compromise Na⁺/H⁺ exchanger function. PloS One. 2016, 11e162902

[344] Fuster DG, Alexander RT. Traditional and emerging roles for the SLC9 Na⁺/H⁺ exchangers. Pflugers Arch.. 2014, 46661-76.

[345] Biemesderfer D, Reilly RF, Exner M, Igarashi P, Aronson PS. Immunocytochemical characterization of Na⁺-H⁺ exchanger isoform NHE-1 in rabbit kidney. Am. J. Physiol.. 1992, 263: F833-F840

[346] Petrecca K, Atanasiu R, Grinstein S, Orlowski J, Shrier A. Subcellular localization of the Na⁺/H⁺ exchanger NHE1 in rat myocardium. Am. J. Physiol.. 1999, 276: H709-H717

[347] Amith SR, Fliegel L. Regulation of the Na⁺/H⁺ exchanger (NHE1) iN Breast Cancer Metastasis. Cancer Res.. 2013, 73: 1259-1264.

[348] Guissart Cet al. . Mutation of SLC9A1, encoding the major Na⁺/H⁺ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome. Hum. Mol. Genet.. 2015, 24: 463-470.

[349] Liu L, Schlesinger PH, Slack NM, Friedman PA, Blair HC. High capacity Na⁺/H⁺ exchange activity in mineralizing osteoblasts. J. Cell. Physiol.. 2011, 226: 1702-1712.

[350] Schnyder Det al. . Deletion of the sodium/hydrogen exchanger 6 causes low bone volume in adult mice. Bone. 2021, 153: 116178.

[351] Lee SHet al. . NHE10, an osteoclast-specific member of the Na⁺/H⁺ exchanger family, regulates osteoclast differentiation and survival [corrected]. Biochem. Biophys. Res. Commun.. 2008, 369320-326.

[352] Mine Yet al. . Inhibition of RANKL-dependent cellular fusion in pre-osteoclasts by amiloride and an NHE10-specific monoclonal antibody. Cell Biol. Int.. 2015, 39: 696-709.

[353] Matsuoka Ret al. . Author Correction: Structure, mechanism and lipid-mediated remodeling of the mammalian Na⁺/H⁺ exchanger NHA2. Nat. Struct. Mol. Biol.. 2023, 30: 565.

[354] Hofstetter W, Siegrist M, Simonin A, Bonny O, Fuster DG. Sodium/hydrogen exchanger NHA2 in osteoclasts: subcellular localization and role in vitro and in vivo. Bone. 2010, 47331-340.

[355] Battaglino RAet al. . NHA-oc/NHA2: a mitochondrial cation-proton antiporter selectively expressed in osteoclasts. Bone. 2008, 42: 180-192.

[356] Ha BGet al. . Proteomic profile of osteoclast membrane proteins: identification of Na⁺/H⁺ exchanger domain containing 2 and its role in osteoclast fusion. Proteomics. 2008, 8: 2625-2639.

[357] Quednau BD, Nicoll DA, Philipson KD. The sodium/calcium exchanger family-SLC8. Pflugers Arch.. 2004, 447: 543-548.

[358] Albano Get al. . Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1). Pflugers Arch.. 2017, 469: 225-233.

[359] Moonga BSet al. . Identification and characterization of a sodium/calcium exchanger, NCX-1, in osteoclasts and its role in bone resorption. Biochem. Biophys. Res. Commun.. 2001, 283: 770-775.

[360] Li Tet al. . NCX1 disturbs calcium homeostasis and promotes RANKL-induced osteoclast differentiation by regulating JNK/c-Fos/NFATc1 signaling pathway in multiple myeloma. Clin. Exper. Med.. 2023, 23: 1581-1596.

[361] Gupta A, Guo XL, Alvarez UM, Hruska KA. Regulation of sodium-dependent phosphate transport in osteoclasts. J. Clin. Invest.. 1997, 100: 538-549.

[362] Gupta Aet al. . Identification of the type II Na⁺-Pi cotransporter (Npt2) in the osteoclast and the skeletal phenotype of Npt2^−/− mice. Bone. 2001, 29: 467-476.

[363] Reimer RJ, Edwards RH. Organic anion transport is the primary function of the SLC17/type I phosphate transporter family. Pflugers Arch.. 2004, 447: 629-635.

[364] Forster IC, Hernando N, Biber J, Murer H. Phosphate transporters of the SLC20 and SLC34 families. Mol. Aspects Med.. 2013, 34: 386-395.

[365] Roman-Fernandez Aet al. . The phospholipid PI(3,4)P(2) is an apical identity determinant. Nat. Commun.. 2018, 9. 5041

[366] Gassama-Diagne Aet al. . Phosphatidylinositol-3,4,5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells. Nat. Cell Biol.. 2006, 8: 963-970.

[367] Albano Get al. . Sodium-dependent phosphate transporters in osteoclast differentiation and function. PloS One. 2015, 10. e125104

[368] Belenky MAet al. . Cell-type-specific distribution of chloride transporters in the rat suprachiasmatic nucleus. Neuroscience. 2010, 165: 1519-1537.

[369] Fujii T, Fujita K, Takeguchi N, Sakai H. Function of K⁺-Cl^- cotransporters in the acid secretory mechanism of gastric parietal cells. Biol. Pharm. Bull.. 2011, 34: 810-812.

[370] Brauer M, Frei E, Claes L, Grissmer S, Jager H. Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl^- channels in human osteoblasts. Am. J. Physiol. Cell Physiol.. 2003, 285: C22-C30.

[371] Jalali Ret al. . The role of Na:K:2Cl cotransporter 1 (NKCC1/SLC12A2) in dental epithelium during enamel formation in mice. Front. Physiol.. 2017, 8: 924.

[372] Kajiya H, Okamoto F, Li J, Nakao A, Okabe K. Expression of mouse osteoclast K-Cl Co-transporter-1 and its role during bone resorption. J. Bone. Miner. Res.. 2006, 21984-992.

[373] Zhao F, Keating AF. Functional properties and genomics of glucose transporters. Curr. Genom.. 2007, 8: 113-128.

[374] Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol. Aspects Med.. 2013, 34: 121-138.

[375] Indo Yet al. . Metabolic regulation of osteoclast differentiation and function. J. Bone. Miner. Res.. 2013, 28: 2392-2399.

[376] Scalise M, Pochini L, Pingitore P, Hedfalk K, Indiveri C. Cysteine is not a substrate but a specific modulator of human ASCT2 (SLC1A5) transporter. FEBS Lett.. 2015, 589: 3617-3623.

[377] Li Bet al. . Both aerobic glycolysis and mitochondrial respiration are required for osteoclast differentiation. FASEB J.. 2020, 34: 11058-11067.

[378] Bartoloni L, Antonarakis SE. The human sugar-phosphate/phosphate exchanger family SLC37. Pflugers Arch.. 2004, 447: 780-783.

[379] Kim JY, Tillison K, Zhou S, Wu Y, Smas CM. The major facilitator superfamily member Slc37a2 is a novel macrophage-specific gene selectively expressed in obese white adipose tissue. Am. J. Physiol.-Endocrinol. Metab.. 2007, 293: E110-E120.

[380] Pan Cet al. . SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphate antiporters. PloS One. 2011, 6: e23157.

[381] Ng PYet al. . Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts. Nat. Commun.. 2023, 14. 906

[382] Young JD, Yao SYM, Baldwin JM, Cass CE, Baldwin SA. The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol. Aspects Med.. 2013, 34529-547.

[383] Huang W, Zeng X, Shi Y, Liu M. Functional characterization of human equilibrative nucleoside transporter 1. Protein Cell. 2017, 8: 284-295.

[384] Katsuyama Set al. . Identification of a novel compound that inhibits osteoclastogenesis by suppressing nucleoside transporters. FEBS Lett.. 2016, 590: 1152-1162.

[385] Vasko Bet al. . Inhibitor selectivity of CNTs and ENTs. Xenobiotica. 2019, 49: 840-851.

[386] Griffith DA, Jarvis SM. Nucleoside and nucleobase transport systems of mammalian cells. Biochim. Biophys. Acta. 1996, 1286: 153-181.

[387] He W, Cronstein B. The roles of adenosine and adenosine receptors in bone remodeling. Front. Biosci. (Elite Ed.). 2011, 3: 888-895

[388] Hinton DJet al. . Aberrant bone density in aging mice lacking the adenosine transporter ENT1. PloS One. 2014, 9. e88818

[389] Kanai Y, Hediger MA. The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. Pflugers Arch.. 2004, 447: 469-479.

[390] Broer A, Rahimi F, Broer S. Deletion of amino acid transporter ASCT2 (SLC1A5) reveals an essential role for transporters SNAT1 (SLC38A1) and SNAT2 (SLC38A2) to sustain glutaminolysis in cancer cells. J. Biol. Chem.. 2016, 291: 13194-13205.

[391] Yu Yet al. . Glutamine metabolism regulates proliferation and lineage allocation in skeletal stem cells. Cell Metab.. 2019, 29: 966-978.

[392] Soe Ket al. . Involvement of human endogenous retroviral syncytin-1 in human osteoclast fusion. Bone. 2011, 48: 837-846.

[393] Mason DJ, Huggett JF. Glutamate transporters in bone. J. Musculoskelet. Neuronal Interact.. 2002, 2: 406-414

[394] Morimoto Ret al. . Secretion of L-glutamate from osteoclasts through transcytosis. EMBO J.. 2006, 25: 4175-4186.

[395] Peng Ret al. . IL-17 promotes osteoclast-induced bone loss by regulating glutamine-dependent energy metabolism. Cell Death Dis.. 2024, 15. 111

[396] Fotiadis D, Kanai Y, Palacin M. The SLC3 and SLC7 families of amino acid transporters. Mol. Aspects Med.. 2013, 34: 139-158.

[397] Zhang Cet al. . SLC3A2 N-glycosylation and Golgi remodeling regulate SLC7A amino acid exchangers and stress mitigation. J. Biol. Chem.. 2023, 299: 105416.

[398] You S, Han X, Xu Y, Yao Q. Research progress on the role of cationic amino acid transporter (CAT) family members in malignant tumors and immune microenvironment. Amino Acids. 2023, 551213-1222.

[399] Verrey Fet al. . CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch.. 2004, 447: 532-542.

[400] Saier MHJ, Yen MR, Noto K, Tamang DG, Elkan C. The Transporter Classification Database: recent advances. Nucleic Acids. Res.. 2009, 37: D274-D278.

[401] Kondo T, Ikeda K, Matsuo K. Detection of osteoclastic cell-cell fusion through retroviral vector packaging. Bone. 2004, 35: 1120-1126.

[402] Liao Yet al. . Single-cell profiling of SLC family transporters: uncovering the role of SLC7A1 in osteosarcoma. J. Transl. Med.. 2025, 23. 103

[403] Kandasamy P, Gyimesi G, Kanai Y, Hediger MA. Amino acid transporters revisited: New views in health and disease. Trends Biochem. Sci.. 2018, 43: 752-789.

[404] Ozaki, K. et al. The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway. Sci. Signal. 12, 589 (2019).

[405] Rivas CIet al. . Vitamin C transporters. J. Physiol. Biochem.. 2008, 64: 357-375.

[406] Eck Pet al. . Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2. Hum. Genet.. 2004, 115: 285-294.

[407] Hie M, Tsukamoto I. Vitamin C-deficiency stimulates osteoclastogenesis with an increase in RANK expression. J. Nutr. Biochem.. 2011, 22: 164-171.

[408] Ragab AA, Lavish SA, Banks MA, Goldberg VM, Greenfield EM. Osteoclast differentiation requires ascorbic acid. J. Bone. Miner. Res.. 1998, 13: 970-977.

[409] Wu X, Itoh N, Taniguchi T, Nakanishi T, Tanaka K. Requirement of calcium and phosphate ions in expression of sodium-dependent vitamin C transporter 2 and osteopontin in MC3T3-E1 osteoblastic cells. Biochim. Biophys. Acta. 2003, 1641: 65-70.

[410] Xiong J, Feng J, Yuan D, Zhou J, Miao W. Tracing the structural evolution of eukaryotic ATP-binding cassette transporter superfamily. Sci. Rep.. 2015, 5. 16724

[411] Schaedler TAet al. . Structures and functions of mitochondrial ABC transporters. Biochem. Soc. Trans.. 2015, 43: 943-951.

[412] Brodeur GM. Knowing your ABCCs: novel functions of ABCC transporters. J. Natl. Cancer. Inst.. 2011, 103: 1207-1208.

[413] Guidotti G. ATP transport and ABC proteins. Chem. Biol. 1996, 3: 703-706.

[414] Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res.. 2001, 42: 1007-1017.

[415] Irie A, Yamamoto K, Miki Y, Murakami M. Phosphatidylethanolamine dynamics are required for osteoclast fusion. Sci. Rep.. 2017, 7. 46715

[416] Huang Xet al. . HDL impairs osteoclastogenesis and induces osteoclast apoptosis via upregulation of ABCG1 expression. Acta Biochim. Biophys. Sin.. 2018, 50: 853-861.

[417] Mourskaia AAet al. . ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone. Breast Cancer Res.. 2012, 14. R149

[418] Kong YYet al. . Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999, 402: 304-309.

[419] Dougall WCet al. . RANK is essential for osteoclast and lymph node development. Genes. Dev.. 1999, 13: 2412-2424.

[420] Negishi-Koga T, Takayanagi H. Ca²⁺-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol. Rev.. 2009, 231: 241-256.

[421] Matsuo Ket al. . Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J. Biol. Chem.. 2004, 279: 26475-26480.

[422] Takito, J., Inoue, S. & Nakamura, M. The sealing zone in osteoclasts: a self-organized structure on the bone. Int. J. Mol. Sci. 19, 984 (2018).

[423] Saltel F, Chabadel A, Bonnelye E, Jurdic P. Actin cytoskeletal organisation in osteoclasts: a model to decipher transmigration and matrix degradation. Eur. J. Cell Biol.. 2008, 87: 459-468.

[424] Nijenhuis T, Hoenderop JGJ, Bindels RJM. TRPV5 and TRPV6 in Ca²⁺ (re)absorption: regulating Ca²⁺ entry at the gate. Pflugers Arch.. 2005, 451: 181-192.

[425] Neubert Pet al. . NCX1 represents an ionic Na+ sensing mechanism in macrophages. PloS Biol.. 2020, 18. e3000722

[426] Mousawi Fet al. . Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling. Stem. Cells.. 2020, 38: 410-421.

[427] Wacquier B, Combettes L, Van Nhieu GT, Dupont G. Interplay between intracellular Ca²⁺ oscillations and Ca²⁺-stimulated mitochondrial metabolism. Sci. Rep.. 2016, 6. 19316

[428] Kartner N, Manolson MF. Novel techniques in the development of osteoporosis drug therapy: the osteoclast ruffled-border vacuolar H⁺-ATPase as an emerging target. Expert. Opin. Drug Discov.. 2014, 9: 505-522.

[429] Osteresch Cet al. . The binding site of the V-ATPase inhibitor apicularen is in the vicinity of those for bafilomycin and archazolid. J. Biol. Chem.. 2012, 287: 31866-31876.

[430] Price PA, June HH, Buckley JR, Williamson MK. SB 242784, a selective inhibitor of the osteoclastic V-H⁺ATPase, inhibits arterial calcification in the rat. Circ. Res.. 2002, 91: 547-552.

[431] Niikura K, Takano M, Sawada M. A novel inhibitor of vacuolar ATPase, FR167356, which can discriminate between osteoclast vacuolar ATPase and lysosomal vacuolar ATPase. Br. J. Pharmacol.. 2004, 142: 558-566.

[432] Sorensen MG, Henriksen K, Neutzsky-Wulff AV, Dziegiel MH, Karsdal MA. Diphyllin, a novel and naturally potent V-ATPase inhibitor, abrogates acidification of the osteoclastic resorption lacunae and bone resorption. J. Bone. Miner. Res.. 2007, 22: 1640-1648.

[433] Lebreton S, Jaunbergs J, Roth MG, Ferguson DA, De Brabander JK. Evaluating the potential of vacuolar ATPase inhibitors as anticancer agents and multigram synthesis of the potent salicylihalamide analog saliphenylhalamide. Bioorg. Med. Chem. Lett.. 2008, 18: 5879-5883.

[434] Xie Xet al. . Salicylihalamide A inhibits the V0 sector of the V-ATPase through a mechanism distinct from bafilomycin A1. J. Biol. Chem.. 2004, 279: 19755-19763.

[435] Kartner Net al. . Inhibition of osteoclast bone resorption by disrupting vacuolar H⁺-ATPase a3-B2 subunit interaction. J. Biol. Chem.. 2010, 285: 37476-37490.

[436] Shin D, Kim M, Lee S, Kim T, Kim S. Inhibitory effects of luteolin on titanium particle-induced osteolysis in a mouse model. Acta Biomater.. 2012, 8: 3524-3531.

[437] Kim Tet al. . The effects of luteolin on osteoclast differentiation, function in vitro and ovariectomy-induced bone loss. J. Nutr. Biochem.. 2011, 22: 8-15.

[438] Lee Jet al. . Inhibitory effect of luteolin on osteoclast differentiation and function. Cytotechnology. 2009, 61: 125-134.

[439] Wang Yet al. . Pharmacological targeting of vacuolar H⁺-ATPase via subunit V1G combats multidrug-resistant cancer. Cell Chem. Biol.. 2020, 27: 1359-1370.

[440] Wang Set al. . Glycolysis-mediated activation of v-ATPase by nicotinamide mononucleotide ameliorates lipid-induced cardiomyopathy by repressing the CD36-TLR4 axis. Circ. Res.. 2024, 134: 505-525.

[441] Dai Tet al. . Unveiling Vacuolar H⁺-ATPase subunit a as the primary target of the pyridinylmethyl-benzamide fungicide, fluopicolide. J. Agric. Food. Chem.. 2024, 72: 1527-1538.

[442] Zhang Xet al. . A key amino acid substitution of vacuolar-type H⁺-ATPases A subunit (VATP-A) confers selective toxicity of a potential botanical insecticide, periplocoside P (PSP), in Mythimna separata and Spodoptera exigua. Insect. Biochem. Mol. Biol.. 2025, 179: 104277.

[443] Song Met al. . Elevated intracellular Ca²⁺ functions downstream of mitodysfunction to induce Wallerian-like degeneration and necroptosis in organophosphorus-induced delayed neuropathy. Toxicology. 2024, 504153812.

[444] Bai J, Liu F, Wu L, Wang Y, Li X. Attenuation of TRPV1 by AMG-517 after nerve injury promotes peripheral axonal regeneration in rats. Mol. Pain.. 2018, 14. 2070385906

[445] Gavva NRet al. . AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties.. J. Pharmacol. Exp. Ther.. 2005, 313474-484.

[446] Dunne OMet al. . TRPV2 modulates mechanically Induced ATP Release from Human bronchial epithelial cells. Respir. Res.. 2024, 25: 188.

[447] Murphy TVet al. . TRPV3 expression and vasodilator function in isolated uterine radial arteries from non-pregnant and pregnant rats. Vasc. Pharmacol.. 2016, 8366-77.

[448] Vincent Fet al. . Identification and characterization of novel TRPV4 modulators. Biochem. Biophys. Res. Commun.. 2009, 389: 490-494.

[449] Cunha MRet al. . Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor. RSC Med. Chem.. 2020, 11: 1032-1040.

[450] Li Qet al. . Transient receptor potential melastatin 7 aggravates necrotizing enterocolitis by promoting an inflammatory response in children. Transl. Pediatr.. 2022, 11: 2030-2039.

[451] Lai P, Michelangeli F. Bis(2-hydroxy-3-tert-butyl-5-methyl-phenyl)-methane (bis-phenol) is a potent and selective inhibitor of the secretory pathway Ca²⁺ ATPase (SPCA1). Biochem. Biophys. Res. Commun.. 2012, 424: 616-619.

[452] Chang Let al. . Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis. Neurobiol. Dis.. 2024, 199: 106573.

[453] Yang Yet al. . Phoenixin 20 promotes neuronal mitochondrial biogenesis via CREB-PGC-1alpha pathway. J. Mol. Histol.. 2020, 51173-181.

[454] Jiang Het al. . Target the human alanine/serine/cysteine transporter 2(ASCT2): achievement and future for novel cancer therapy. Pharmacol. Res.. 2020, 158: 104844.

[455] Broer A, Fairweather S, Broer S. Disruption of amino acid homeostasis by novel ASCT2 inhibitors involves multiple targets. Front. Pharmacol.. 2018, 9785.

[456] Kurth Iet al. . Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels. Sci. Adv.. 2021, 7. eabi7511

[457] Montalbetti N, Simonin A, Dalghi MG, Kovacs G, Hediger MA. Development and validation of a fast and homogeneous cell-based fluorescence screening assay for divalent metal transporter 1 (DMT1/SLC11A2) using the FLIPR Tetra. J. Biomol. Screen. 2014, 19900-908.

[458] Fujii Tet al. . Functional association between K⁺-Cl^- cotransporter-4 and H⁺, K⁺-ATPase in the apical canalicular membrane of gastric parietal cells. J. Biol. Chem.. 2009, 284: 619-629.

[459] Cao X, Lenk GM, Mikusevic V, Mindell JA, Meisler MH. The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG4 and VAC14 mutants. PloS Genet.. 2023, 19. e1010800

[460] Olotu Fet al. . Structure-based discovery and in vitro validation of inhibitors of chloride intracellular channel 4 protein. Comp. Struct. Biotechnol. J.. 2023, 21: 688-701.

[461] Stewart AK, Kurschat CE, Vaughan-Jones RD, Shmukler BE, Alper SL. Acute regulation of mouse AE2 anion exchanger requires isoform-specific amino acid residues from most of the transmembrane domain. J. Physiol.. 2007, 584: 59-73.

[462] Keiter Set al. . Does perfluorooctane sulfonate (PFOS) act as chemosensitizer in zebrafish embryos?. Sci. Total Environ.. 2016, 548-549: 317-324.

[463] Vagiannis Det al. . Alisertib shows negligible potential for perpetrating pharmacokinetic drug-drug interactions on ABCB1, ABCG2 and cytochromes P450, but acts as dual-activity resistance modulator through the inhibition of ABCC1 transporter. Toxicol. Appl. Pharmacol.. 2022, 434: 115823.

[464] Tong Set al. . Restoration of miR-299-3p promotes macrophage phagocytosis and suppresses malignant phenotypes in breast cancer carcinogenesis via dual-targeting CD47 and ABCE1. Int. Immunopharmacol.. 2024, 130111708.

[465] Pafumi Iet al. . Naringenin impairs two-pore channel 2 activity and inhibits VEGF-induced angiogenesis. Sci. Rep.. 2017, 7. 5121

[466] Chassagnon IRet al. . Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proc. Natl. Acad. Sci. USA. 2017, 1143750-3755.

[467] Wareham K, Vial C, Wykes RCE, Bradding P, Seward EP. Functional evidence for the expression of P2X1, P2X4 and P2X7 receptors in human lung mast cells. Br. J. Pharmacol.. 2009, 157: 1215-1224.

[468] Huang Het al. . The potential of the P2X7 receptor as a therapeutic target in a sub-chronic PCP-induced rodent model of schizophrenia. J. Chem. Neuroanat.. 2021, 116: 101993.

[469] Olov Net al. . Using Nanoscale Passports To Understand and Unlock Ion Channels as Gatekeepers of the Cell.. Acs Nano.. 2024, 1822709-22733.

[470] Zhou R, Fu W, Vasylyev D, Waxman SG, Liu C. Ion channels in osteoarthritis: emerging roles and potential targets. Nat. Rev. Rheumatol.. 2024, 20: 545-564.

[471] DeJulius CRet al. . Engineering approaches for RNA-based and cell-based osteoarthritis therapies. Nat. Rev. Rheumatol.. 2024, 20: 81-100.

[472] Jackson TCet al. . PPAR alpha agonists improve renal preservation in kidneys subjected to chronic in vitro perfusion: interaction with mannitol. Transpl. Int.. 2007, 20: 277-290.

[473] Hong JHet al. . Markers of squamous cell carcinoma in sarco/endoplasmic reticulum Ca²⁺ ATPase 2 heterozygote mice keratinocytes. Prog. Biophys. Mol. Biol.. 2010, 103: 81-87.

[474] Hynes D, Harvey BJ. Dexamethasone reduces airway epithelial Cl^- secretion by rapid non-genomic inhibition of KCNQ1, KCNN4 and KATP K⁺ channels. Steroids. 2019, 151: 108459.

[475] Bobi Jet al. . Kv1.3 blockade inhibits proliferation of vascular smooth muscle cells in vitro and intimal hyperplasia in vivo. Transl. Res.. 2020, 22440-54.

[476] Rodriguez-Prados Met al. . MICU1 controls the sensitivity of the mitochondrial Ca²⁺ uniporter to activators and inhibitors. Cell Chem. Biol.. 2023, 30: 606-617.

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82370907, 81974145，81470728)

RIGHTS & PERMISSIONS

The Author(s)