Small-molecule amines: a big role in the regulation of bone homeostasis

Abstract

Numerous small-molecule amines (SMAs) play critical roles in maintaining bone homeostasis and promoting bone regeneration regardless of whether they are applied as drugs or biomaterials. On the one hand, SMAs promote bone formation or inhibit bone resorption through the regulation of key molecular signaling pathways in osteoblasts/osteoclasts; on the other hand, owing to their alkaline properties as well as their antioxidant and anti-inflammatory features, most SMAs create a favorable microenvironment for bone homeostasis. However, due to a lack of information on their structure/bioactivity and underlying mechanisms of action, certain SMAs cannot be developed into drugs or biomaterials for bone disease treatment. In this review, we thoroughly summarize the current understanding of SMA effects on bone homeostasis, including descriptions of their classifications, biochemical features, recent research advances in bone biology and related regulatory mechanisms in bone regeneration. In addition, we discuss the challenges and prospects of SMA translational research.

References

[1] Moller AMJ et al. Aging and menopause reprogram osteoclast precursors for aggressive bone resorption. Bone Res., 2020, 8: 27

[2] Modinger Y, Loffler B, Huber-Lang M, Ignatius A. Complement involvement in bone homeostasis and bone disorders. Semin. Immunol., 2018, 37: 53-65

[3] Liao J, Han R, Wu Y, Qian Z. Review of a new bone tumor therapy strategy based on bifunctional biomaterials. Bone Res., 2021, 9: 18

[4] Wiese A, Pape HC. Bone defects caused by high-energy injuries, bone loss, infected nonunions, and nonunions. Orthop. Clin. North Am., 2010, 41: 1-4 table of contents

[5] Zhang Y, Luo G, Yu X. Cellular communication in bone homeostasis and the related anti-osteoporotic drug development. Curr. Med. Chem., 2020, 27: 1151-1169

[6] Chen D et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res., 2017, 5: 16044

[7] Salhotra A, Shah HN, Levi B, Longaker MT. Mechanisms of bone development and repair. Nat. Rev. Mol. Cell Biol., 2020, 21: 696-711

[8] Chen H, Senda T, Kubo KY. The osteocyte plays multiple roles in bone remodeling and mineral homeostasis. Med. Mol. Morphol., 2015, 48: 61-68

[9] Feng X, Teitelbaum SL. Osteoclasts: new insights. Bone Res., 2013, 1: 11-26

[10] Walker DG. Osteopetrosis cured by temporary parabiosis. Science, 1973, 180: 875

[11] Zambonin Zallone A, Teti A, Primavera MV. Monocytes from circulating blood fuse in vitro with purified osteoclasts in primary culture. J. Cell Sci., 1984, 66: 335-342

[12] Søe K et al. Coordination of fusion and trafficking of pre-osteoclasts at the marrow-bone interface. Calcif. Tissue Int., 2019, 105: 430-445

[13] MacDonald BR et al. Effects of human recombinant CSF-GM and highly purified CSF-1 on the formation of multinucleated cells with osteoclast characteristics in long-term bone marrow cultures. J. Bone Min. Res., 1986, 1: 227-233

[14] Udagawa N et al. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc. Natl. Acad. Sci. USA, 1990, 87: 7260-7264

[15] Wiktor-Jedrzejczak W et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl. Acad. Sci. USA, 1990, 87: 4828-4832

[16] Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol., 2004, 14: 628-638

[17] McDonald MM et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell, 2021, 184: 1-18

[18] Hardy R, Cooper MS. Bone loss in inflammatory disorders. J. Endocrinol., 2009, 201: 309-320

[19] Callaway DA, Jiang JX. Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. J. Bone Min. Metab., 2015, 33: 359-370

[20] Arnett TR. Extracellular pH regulates bone cell function. J. Nutr., 2008, 138: 415S-418S

[21] Macielag, M. J. Antibiotic Discovery and Development (eds T. J. Dougherty & M. J. Pucci) 793–819 (Springer New York, NY, 2011).

[22] Momeni A, Rapp S, Donneys A, Buchman SR, Wan DC. Clinical use of deferoxamine in distraction osteogenesis of irradiated bone. J. Craniofac. Surg., 2016, 27: 880-882

[23] Wang L et al. Dopamine suppresses osteoclast differentiation via cAMP/PKA/CREB pathway. Cell Signal., 2021, 78: 109847

[24] Gu L, Ke Y, Gan J, Li X. Berberine suppresses bone loss and inflammation in ligature-induced periodontitis through promotion of the G protein-coupled estrogen receptor-mediated inactivation of the p38MAPK/NF-kappaB pathway. Arch. Oral. Biol., 2020, 122: 104992-104992

[25] Wang L et al. Tetramethylpyrazine protects against glucocorticoid-induced apoptosis by promoting autophagy in mesenchymal stem cells and improves bone mass in glucocorticoid-induced osteoporosis rats. Stem Cells Dev., 2017, 26: 419-430

[26] 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

[27] Adam S et al. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci. Transl. Med., 2020, 12: eaay4447

[28] Vidal B et al. Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model. Rheumatology, 2018, 57: 1461-1471

[29] Chandra A et al. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. FASEB J., 2018, 32: 52-62

[30] Shaik AR et al. Metformin: is it the well wisher of bone beyond glycemic control in diabetes mellitus? Calcif. Tissue Int., 2021, 108: 693-707

[31] Ma P et al. Glimepiride promotes osteogenic differentiation in rat osteoblasts via the PI3K/Akt/eNOS pathway in a high glucose microenvironment. PLoS One, 2014, 9: e112243

[32] S. L., Taylor & S. L., Hefle. Foodborne Diseases (eds C. E. R. Dodd et al.) 327–344 (Academic Press, 2017).

[33] Zhu MP et al. Vinpocetine inhibits RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss. Biomed. Pharmacother., 2020, 123: 10

[34] Jin H, Yao L, Chen K. Evodiamine inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in mice. J. Cell. Mol. Med., 2019, 23: 4850-4850

[35] Zeng XZ et al. Aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing NF-kappa B and NFATc1 activation and DC-STAMP expression. Acta Pharmacol. Sin., 2016, 37: 255-263

[36] Ouellette, R. J. & Rawn, J. D. Organic Chemistry (eds R. J. Ouellette & J. David Rawn) 803–842 (Elsevier, 2014).

[37] Lovaas E. Antioxidative and metal-chelating effects of polyamines. Adv. Pharm., 1997, 38: 119-149

[38] Zhou T, Wang P, Gu Z, Ma M, Yang R. Spermidine improves antioxidant activity and energy metabolism in mung bean sprouts. Food Chem., 2020, 309: 125759

[39] Drugbank online. Odanacatib, <https://go.drugbank.com/drugs/DB06670> (2022).

[40] Kim SH et al. Bortezomib prevents ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation. J. Bone Min. Metab., 2018, 36: 537-546

[41] de Vries TJ et al. The Src inhibitor AZD0530 reversibly inhibits the formation and activity of human osteoclasts. Mol. Cancer Res., 2009, 7: 476-488

[42] Yang JC et al. Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol. Cancer Ther., 2010, 9: 1629-1637

[43] Jiao H, Xiao E, Graves DT. Diabetes and its effect on bone and fracture healing. Curr. Osteoporos. Rep., 2015, 13: 327-335

[44] Lecka-Czernik B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia, 2017, 60: 1163-1169

[45] Son HS et al. Benzydamine inhibits osteoclast differentiation and bone resorption via down-regulation of interleukin-1 beta expression. Acta Pharm. Sin. B, 2020, 10: 462-474

[46] Aasarod KM et al. Effects of the histamine 1 receptor antagonist cetirizine on the osteoporotic phenotype in H+/K(+)ATPase beta subunit KO mice. J. Cell. Biochem., 2016, 117: 2089-2096

[47] Yamaura K, Yonekawa T, Nakamura T, Yano S, Ueno K. The histamine H-2-receptor antagonist, cimetidine, inhibits the articular osteopenia in rats with adjuvant-induced arthritis by suppressing the osteoclast differentiation induced by histamine. J. Pharmacol. Sci., 2003, 92: 43-49

[48] Gomes PS, Resende M, Fernandes MH. Doxycycline restores the impaired osteogenic commitment of diabetic-derived bone marrow mesenchymal stromal cells by increasing the canonical WNT signaling. Mol. Cell Endocrinol., 2020, 518: 110975

[49] Drugbank online. Lidocaine, <https://go.drugbank.com/drugs/DB00281>(2021).

[50] Li L et al. Polydopamine coating promotes early osteogenesis in 3D printing porous Ti6Al4V scaffolds. Ann. Transl. Med., 2019, 7: 14

[51] Hu C et al. Berberine/Ag nanoparticle embedded biomimetic calcium phosphate scaffolds for enhancing antibacterial function. Nanotechnol. Rev., 2020, 9: 568-579

[52] Sang S, Wang SJ, Yang C, Geng Z, Zhang XL. Sponge-inspired sulfonated polyetheretherketone loaded with polydopamine-protected osthole nanoparticles and berberine enhances osteogenic activity and prevents implant-related infections. Chem. Eng. J., 2022, 437: 135255

[53] Chen H, Yan YF, Qi J, Deng LF, Cui WG. Sustained delivery of desferrioxamine via liposome carriers in hydrogel for combining angiogenesis and osteogenesis in bone defects reconstruction. J. Control. Release, 2017, 259: E79-E79

[54] Song W et al. Doxycycline-loaded coaxial nanofiber coating of titanium implants enhances osseointegration and inhibits Staphylococcus aureus infection. Biomed. Mater., 2017, 12: 045008

[55] Wang D, Zhang P, Mei X, Chen Z. Repair calvarial defect of osteoporotic rats by berberine functionalized porous calcium phosphate scaffold. Regen. Biomater., 2021, 8: 10

[56] Ozturk-Oncel MO, Odabas S, Uzun L, Hur D, Garipcan B. A facile surface modification of poly(dimethylsiloxane) with amino acid conjugated self-assembled monolayers for enhanced osteoblast cell behavior. Colloids Surf. B Biointerfaces, 2020, 196: 111343

[57] Cui N, Han K, Li M, Wang J, Qian J. Pure polylysine-based foamy scaffolds and their interaction with MC3T3-E1 cells and osteogenesis. Biomed. Mater., 2020, 15: 025004

[58] Ma Y et al. Three-dimensional printing of biodegradable piperazine-based polyurethane-urea scaffolds with enhanced osteogenesis for bone regeneration. ACS Appl. Mater. Interfaces, 2019, 11: 9415-9424

[59] Mao L et al. Regulation of inflammatory response and osteogenesis to citrate-based biomaterials through incorporation of alkaline fragments. Adv. Health. Mater., 2022, 11: e2101590

[60] Pritchard JJ. A cytological and histochemical study of bone and cartilage formation in the rat. J. Anat., 1952, 86: 259-277

[61] Young MF, Kerr JM, Ibaraki K, Heegaard AM, Robey PG. Structure, expression, and regulation of the major noncollagenous matrix proteins of bone. Clin. Orthop. Relat. Res., 1992, 281: 275-294

[62] Robey PG et al. Structure and molecular regulation of bone matrix proteins. J. Bone Min. Res., 1993, 8: S483-S487

[63] Long F. Building strong bones: molecular regulation of the osteoblast lineage. Nat. Rev. Mol. Cell Biol., 2011, 13: 27-38

[64] Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature, 2001, 410: 37-40

[65] Jaiswal RK et al. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J. Biol. Chem., 2000, 275: 9645-9652

[66] Kim JM et al. The ERK MAPK pathway is essential for skeletal development and homeostasis. Int. J. Mol. Sci., 2019, 20: 1803

[67] Wang CX et al. Dopamine D1 receptor-mediated activation of the ERK signaling pathway is involved in the osteogenic differentiation of bone mesenchymal stem cells. Stem Cell Res. Ther., 2020, 11: 13

[68] Lee HW et al. Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J. Bone Min. Res., 2008, 23: 1227-1237

[69] Xin BC et al. Berberine promotes osteogenic differentiation of human dental pulp stem cells through activating EGFR-MAPK-Runx2 pathways. Pathol. Oncol. Res., 2020, 26: 1677-1685

[70] Kim DS et al. Effects of glutamine on proliferation, migration, and differentiation of human dental pulp cells. J. Endod., 2014, 40: 1087-1094

[71] Yin H et al. Preventive effects of evodiamine on dexamethasone-induced osteoporosis in zebrafish. Biomed. Res. Int., 2019, 2019: 6

[72] Kim HK et al. Salicylideneamino-2-thiophenol enhances osteogenic differentiation through the activation of MAPK pathways in multipotent bone marrow stem cell. J. Cell. Biochem., 2012, 113: 1833-1841

[73] Chan YH et al. Melatonin enhances osteogenic differentiation of dental pulp mesenchymal stem cells by regulating MAPK pathways and promotes the efficiency of bone regeneration in calvarial bone defects. Stem Cell Res. Ther., 2022, 13: 73

[74] Yuan LQ et al. Taurine promotes connective tissue growth factor (CTGF) expression in osteoblasts through the ERK signal pathway. Amino Acids, 2007, 32: 425-430

[75] Villa I et al. Betaine promotes cell differentiation of human osteoblasts in primary culture. J. Transl. Med., 2017, 15

[76] Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med., 2013, 19: 179-192

[77] Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169: 985-999

[78] Madan B et al. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res., 2018, 6: 17

[79] Zhang LN et al. Berberine improves advanced glycation end products‑induced osteogenic differentiation responses in human periodontal ligament stem cells through the canonical Wnt/β‑catenin pathway. Mol. Med. Rep., 2019, 19: 5440-5452

[80] Yang L et al. Leonurine hydrochloride promotes osteogenic differentiation and increases osteoblastic bone formation in ovariectomized mice by Wnt/beta-catenin pathway. Biochem. Biophys. Res. Commun., 2018, 504: 941-948

[81] Li C et al. The protective effect of piperine on ovariectomy induced bone loss in female mice and its enhancement effect of osteogenic differentiation via Wnt/β-catenin signaling pathway. J. Funct. Food, 2019, 58: 138-150

[82] Karner CM, Esen E, Okunade AL, Patterson BW, Long F. Increased glutamine catabolism mediates bone anabolism in response to WNT signaling. J. Clin. Investig., 2015, 125: 551-562

[83] Seidlitz EP, Sharma MK, Singh G. Extracellular glutamate alters mature osteoclast and osteoblast functions. Can. J. Physiol. Pharm., 2010, 88: 929-936

[84] Schaffer S, Kim HW. Effects and mechanisms of taurine as a therapeutic agent. Biomol. Ther., 2018, 26: 225-241

[85] Prideaux M, Kitase Y, Kimble M, O’Connell TM, Bonewald LF. Taurine, an osteocyte metabolite, protects against oxidative stress-induced cell death and decreases inhibitors of the Wnt/beta-catenin signaling pathway. Bone, 2020, 137: 115374

[86] Ma ZP, Liao JC, Zhao C, Cai DZ. Effects of the 1, 4-dihydropyridine L-type calcium channel blocker benidipine on bone marrow stromal cells. Cell Tissue Res., 2015, 361: 467-476

[87] Ma J, Zhang ZL, Hu XT, Wang XT, Chen AM. Metformin promotes differentiation of human bone marrow derived mesenchymal stem cells into osteoblast via GSK3beta inhibition. Eur. Rev. Med. Pharm. Sci., 2018, 22: 7962-7968

[88] Zhao XE et al. 6-Bromoindirubin-3’-oxime promotes osteogenic differentiation of canine BMSCs through inhibition of GSK3beta activity and activation of the Wnt/beta-catenin signaling pathway. Acad. Bras. Cienc., 2019, 91: e20180459

[89] Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu. Rev. Biochem., 1998, 67: 481-507

[90] Chen J, Crawford R, Chen C, Xiao Y. The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng. Part B Rev., 2013, 19: 516-528

[91] Zhao B et al. Leonurine promotes the osteoblast differentiation of Rat BMSCs by activation of autophagy via the PI3K/Akt/mTOR pathway. Front. Bioeng. Biotechnol., 2021, 9: 615191

[92] Mirones I et al. Dopamine mobilizes mesenchymal progenitor cells through D2-class receptors and their PI3K/AKT pathway. Stem Cells, 2014, 32: 2529-2538

[93] Ma P et al. Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism, 2010, 59: 359-366

[94] Evans BAJ et al. Human osteoblast precursors produce extracellular adenosine, which modulates their secretion of IL-6 and osteoprotegerin. J. Bone Miner. Res., 2006, 21: 228-236

[95] Gharibi B, Abraham AA, Ham J, Evans BAJ. Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. J. Bone Miner. Res., 2011, 26: 2112-2124

[96] Carroll SH et al. A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J. Biol. Chem., 2012, 287: 15718-15727

[97] Borhani S, Corciulo C, Larranaga-Vera A, Cronstein BN. Adenosine A(2A) receptor (A2AR) activation triggers Akt signaling and enhances nuclear localization of beta-catenin in osteoblasts. FASEB J., 2019, 33: 7555-7562

[98] Ryu J et al. Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J., 2006, 25: 5840-5851

[99] Grey A et al. The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. Endocrinology, 2002, 143: 4755-4763

[100] Matsuzaki E et al. Sphingosine-1-phosphate promotes the nuclear translocation of beta-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines. Bone, 2013, 55: 315-324

[101] Endo H, Nito C, Kamada H, Nishi T, Chan PH. Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J. Cereb. Blood Flow. Metab., 2006, 26: 1479-1489

[102] Pantovic A et al. Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone, 2013, 52: 524-531

[103] Chava S, Chennakesavulu S, Gayatri BM, Reddy ABM. A novel phosphorylation by AMP-activated kinase regulates RUNX2 from ubiquitination in osteogenesis over adipogenesis. Cell Death Dis., 2018, 9

[104] Adil M, Mansoori MN, Singh D, Kandhare AD, Sharma M. Pioglitazone-induced bone loss in diabetic rats and its amelioration by berberine: a portrait of molecular crosstalk. Biomed. Pharmacother., 2017, 94: 1010-1019

[105] Kim DY, Kim EJ, Jang WG. Piperine induces osteoblast differentiation through AMPK-dependent Runx2 expression. Biochem. Biophys. Res. Commun., 2018, 495: 1497-1502

[106] Zhang FZ, Xie JL, Wang GL, Zhang G, Yang HL. Anti-osteoporosis activity of Sanguinarine in preosteoblast MC3T3-E1 cells and an ovariectomized rat model. J. Cell. Physiol., 2018, 233: 4626-4633

[107] Zhao X et al. Metformin enhances osteogenic differentiation of stem cells from human-exfoliated deciduous teeth through AMPK pathway. J. Tissue Eng. Regen. Med., 2020, 14: 1869-1879

[108] Xu D et al. OSU53 rescues human OB-6 osteoblastic cells from dexamethasone through activating AMPK signaling. PLoS One, 2016, 11: e0162694

[109] Kim JE et al. AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast. Bone, 2008, 43: 394-404

[110] Zhu Y, Zhou J, Ao R, Yu B. A-769662 protects osteoblasts from hydrogen dioxide-induced apoptosis through activating of AMP-activated protein kinase (AMPK). Int. J. Mol. Sci., 2014, 15: 11190-11203

[111] Liu W et al. Targeted activation of AMPK by GSK621 ameliorates H₂O₂-induced damages in osteoblasts. Oncotarget, 2017, 8: 10543-10552

[112] Wu YH, Li Q, Li P, Liu B. GSK621 activates AMPK signaling to inhibit LPS-induced TNFalpha production. Biochem. Biophys. Res. Commun., 2016, 480: 289-295

[113] Rankin EB et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell, 2012, 149: 63-74

[114] Stegen S et al. HIF-1 alpha promotes glutamine-mediated redox homeostasis and glycogen-dependent bioenergetics to support postimplantation bone cell survival. Cell Metab., 2016, 23: 265-279

[115] Jing XZ et al. Desferoxamine protects against glucocorticoid-induced osteonecrosis of the femoral head via activating HIF-1 alpha expression. J. Cell. Physiol., 2020, 235: 9864-9875

[116] Chen J, Long F. mTOR signaling in skeletal development and disease. Bone Res., 2018, 6: 1

[117] Lv C et al. Glucosamine promotes osteoblast proliferation by modulating autophagy via the mammalian target of rapamycin pathway. Biomed. Pharmacother., 2018, 99: 271-277

[118] Ma YH et al. Glucosamine promotes chondrocyte proliferation via the Wnt/beta-catenin signaling pathway. Int. J. Mol. Med., 2018, 42: 61-70

[119] Sun J et al. Histone demethylase LSD1 regulates bone mass by controlling WNT7B and BMP2 signaling in osteoblasts. Bone Res., 2018, 6: 14

[120] Yonezawa T et al. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling. Biochem. Biophys. Res. Commun., 2011, 409: 260-265

[121] Liang C, Sun RX, Xu YF, Geng W, Li J. Effect of the abnormal expression of BMP-4 in the blood of diabetic patients on the osteogenic differentiation potential of alveolar BMSCs and the rescue effect of metformin: a bioinformatics-based study. Biomed. Res. Int., 2020, 2020: 19

[122] Li HW et al. γ-Aminobutyric acid promotes osteogenic differentiation of mesenchymal stem cells by inducing TNFAIP3. Curr. Gene Ther., 2020, 20: 152-161

[123] Wu X, Walker J, Zhang J, Ding S, Schultz PG. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. Chem. Biol., 2004, 11: 1229-1238

[124] Zhou T, Yang YQ, Chen QM, Xie L. Glutamine metabolism is essential for stemness of bone marrow mesenchymal stem cells and bone homeostasis. Stem Cells Int., 2019, 2019: 13

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

[126] Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell, 1991, 64: 693-702

[127] Marzia M et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J. Cell Biol., 2000, 151: 311-320

[128] Peruzzi B et al. c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nat. Commun., 2012, 3

[129] Garcia-Gomez A et al. Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects. PLoS One, 2012, 7: e34914

[130] Nie P et al. Dasatinib promotes chondrogenic differentiation of human mesenchymal stem cells via the Src/Hippo-YAP signaling pathway. ACS Biomater. Sci. Eng., 2019, 5: 5255-5265

[131] Wang L et al. Antiosteoporotic effects of tetramethylpyrazine via promoting osteogenic differentiation and inhibiting osteoclast formation. Mol. Med. Rep., 2017, 16: 8307-8314

[132] Liu FL, Chen CL, Lai CC, Lee CC, Chang DM. Arecoline suppresses RANKL-induced osteoclast differentiation in vitro and attenuates LPS-induced bone loss in vivo. Phytomedicine, 2020, 69: 11

[133] Jo YJ et al. Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis. J. Cell Physiol., 2021, 236: 1854-1865

[134] Takayanagi H. RANKL as the master regulator of osteoclast differentiation. J. Bone Min. Metab., 2021, 39: 13-18

[135] Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J. Biol. Chem., 2000, 275: 31155-31161

[136] Li HW et al. Sanguinarine inhibits osteoclast formation and bone resorption via suppressing RANKL-induced activation of NF-kappa B and ERK signaling pathways. Biochem. Biophys. Res. Commun., 2013, 430: 951-956

[137] Deepak V, Kruger MC, Joubert A, Coetzee M. Piperine alleviates osteoclast formation through the p38/c-Fos/NFATc1 signaling axis. Biofactors, 2015, 41: 403-413

[138] Zhang J et al. Deferoxamine inhibits iron-uptake stimulated osteoclast differentiation by suppressing electron transport chain and MAPKs signaling. Toxicol. Lett., 2019, 313: 50-59

[139] Wei ZF et al. Norisoboldine suppresses osteoclast differentiation through preventing the accumulation of TRAF6-TAK1 complexes and activation of MAPKs/NF-kappa B/c-Fos/NFATc1 pathways. PLoS One, 2013, 8: 16

[140] Qian Z et al. Cytisine attenuates bone loss of ovariectomy mouse by preventing RANKL-induced osteoclastogenesis. J. Cell Mol. Med., 2020, 24: 10112-10127

[141] Zhi X et al. l-tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK-TRAF6 interactions and inhibiting NF-kappa B and MAPK pathways. J. Cell. Mol. Med., 2020, 24: 785-798

[142] Matsushita T et al. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol. Cell Biol., 2009, 29: 5843-5857

[143] Karin M. Nuclear factor-kappaB in cancer development and progression. Nature, 2006, 441: 431-436

[144] Franzoso G et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev., 1997, 11: 3482-3496

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

[146] Kong YY et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 1999, 397: 315-323

[147] Kong YY, Boyle WJ, Penninger JM. Osteoprotegerin ligand: a common link between osteoclastogenesis, lymph node formation and lymphocyte development. Immunol. Cell Biol., 1999, 77: 188-193

[148] Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol., 2007, 7: 292-304

[149] Chen X, Zhi X, Wang J, Su J. RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation. Bone Res., 2018, 6: 34

[150] Yamashita T et al. NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J. Biol. Chem., 2007, 282: 18245-18253

[151] Song C et al. Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation. FASEB J., 2020, 34: 4798-4811

[152] Kang EJ et al. Liensinine and nuciferine, bioactive components of nelumbo nucifera, inhibit the growth of breast cancer cells and breast cancer-associated bone loss. Evid. Based Complement. Altern. Med., 2017, 2017: 1583185

[153] Chen S et al. Neferine suppresses osteoclast differentiation through suppressing NF-kappaB signal pathway but not MAPKs and promote osteogenesis. J. Cell Physiol., 2019, 234: 22960-22971

[154] Hu B et al. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency-induced bone mass loss by modulating TRAF6-mediated signaling. Faseb J., 2019, 33: 2574-2586

[155] Yun J, Lee KY, Park B. Neotuberostemonine inhibits osteoclastogenesis via blockade of NF-kappa B pathway. Biochimie, 2019, 157: 81-91

[156] Takahashi T et al. Tetrandrine prevents bone loss in sciatic-neurectomized mice and inhibits receptor activator of nuclear factor kappa B ligand-induced osteoclast differentiation. Biol. Pharm. Bull., 2012, 35: 1765-1774

[157] Liu Z et al. Tetrandrine inhibits titanium particle-induced inflammatory osteolysis through the nuclear factor-kappaB pathway. Mediat. Inflamm., 2020, 2020: 1926947

[158] Zhong ZY et al. Tetrandrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis. Front. Pharmacol., 2020, 10: 14

[159] Wei ZF et al. Norisoboldine, an anti-arthritis alkaloid isolated from radix linderae, attenuates osteoclast differentiation and inflammatory bone erosion in an aryl hydrocarbon receptor-dependent manner. Int. J. Biol. Sci., 2015, 11: 1113-1126

[160] Guo J et al. Meclizine prevents ovariectomy-induced bone loss and inhibits osteoclastogenesis partially by upregulating PXR. Front. Pharm., 2017, 8: 693

[161] Yamamoto T et al. The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. Br. J. Pharm., 2012, 166: 1084-1096

[162] Zhao H et al. Berberine ameliorates cartilage degeneration in interleukin-1beta-stimulated rat chondrocytes and in a rat model of osteoarthritis via Akt signalling. J. Cell Mol. Med., 2014, 18: 283-292

[163] Moon JB et al. Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J. Immunol., 2012, 188: 163-169

[164] Meng JH et al. Stachydrine prevents LPS-induced bone loss by inhibiting osteoclastogenesis via NF-kappa B and Akt signalling. J. Cell. Mol. Med., 2019, 23: 6730-6743

[165] Li ST et al. SC79 rescues osteoblasts from dexamethasone though activating Akt-Nrf2 signaling. Biochem. Biophys. Res. Commun., 2016, 479: 54-60

[166] Zhu R, Chen YX, Ke QF, Gao YS, Guo YP. SC79-loaded ZSM-5/chitosan porous scaffolds with enhanced stem cell osteogenic differentiation and bone regeneration. J. Mater. Chem. B, 2017, 5: 5009-5018

[167] Hua P et al. Diaporisoindole E inhibits RANKL-induced osteoclastogenesis via suppression of PI3K/AKT and MAPK signal pathways. Phytomedicine, 2020, 75: 8

[168] Holliday LS. Vacuolar H(+)-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments. Biotarget, 2017, 1: 1-14

[169] Blair HC, Teitelbaum SL, Ghiselli R, Gluck S. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science, 1989, 245: 855-857

[170] 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

[171] Visentin L et al. A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J. Clin. Investig., 2000, 106: 309-318

[172] 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

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

[174] Toro EJ et al. Enoxacin directly inhibits osteoclastogenesis without inducing apoptosis. J. Biol. Chem., 2012, 287: 17894-17904

[175] Yamaguchi N et al. Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling. FEBS Lett., 2008, 582: 451-456

[176] Uemura T et al. Epinephrine accelerates osteoblastic differentiation by enhancing bone morphogenetic protein signaling through a cAMP/protein kinase A signaling pathway. Bone, 2010, 47: 756-765

[177] Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat. Rev. Rheumatol., 2012, 8: 133-143

[178] Jimi E et al. Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells. Exp. Cell Res., 1999, 247: 84-93

[179] Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J. Biol. Chem., 2000, 275: 4858-4864

[180] Liu XH, Kirschenbaum A, Yao S, Levine AC. Cross-talk between the interleukin-6 and prostaglandin E(2) signaling systems results in enhancement of osteoclastogenesis through effects on the osteoprotegerin/receptor activator of nuclear factor-{kappa}B (RANK) ligand/RANK system. Endocrinology, 2005, 146: 1991-1998

[181] Marcu KB, Otero M, Olivotto E, Borzi RM, Goldring MB. NF-kappaB signaling: multiple angles to target OA. Curr. drug targets, 2010, 11: 599-613

[182] Lin TH et al. NF-kappaB as a therapeutic target in inflammatory-associated bone diseases. Adv. Protein Chem. Struct. Biol., 2017, 107: 117-154

[183] Wojdasiewicz P, Poniatowski LA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat. Inflamm., 2014, 2014: 561459

[184] Chen Z et al. Spermidine activates RIP1 deubiquitination to inhibit TNF-alpha-induced NF-kappaB/p65 signaling pathway in osteoarthritis. Cell Death Dis., 2020, 11

[185] Gao B et al. Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti-inflammatory and angiogenic environment in aging mice. Aging Cell, 2018, 17: e12741

[186] Yu T, Qu J, Wang Y, Jin H. Ligustrazine protects chondrocyte against IL-1beta induced injury by regulation of SOX9/NF-kappaB signaling pathway. J. Cell Biochem., 2018, 119: 7419-7430

[187] Duan Y, An W, Wu Y, Wang J. Tetramethylpyrazine reduces inflammation levels and the apoptosis of LPSstimulated human periodontal ligament cells via the downregulation of miR302b. Int. J. Mol. Med., 2020, 45: 1918-1926

[188] Wong SK, Chin KY, Ima-Nirwana S. Berberine and musculoskeletal disorders: the therapeutic potential and underlying molecular mechanisms. Phytomedicine, 2020, 73: 152892

[189] Park HJ, Zadeh MG, Suh JH, Choi HS. Dauricine protects from LPS-induced bone loss via the ROS/PP2A/NF-kappa B Axis in osteoclasts. Antioxidants, 2020, 9: 15

[190] Tajima Y et al. Nitensidine A, a guanidine alkaloid from Pterogyne nitens, induces osteoclastic cell death. Cytotechnology, 2015, 67: 585-592

[191] Drug Databases. Drugs@FDA: FDA-Approved Drugs, <https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=207924> (2018).

[192] Drug Databases. Drugs@FDA: FDA-Approved Drugs, <https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=203214> (2012).

[193] Yoshikawa R, Abe K. The multi-kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis. Cell Biochem. Funct., 2021, 39: 521-527

[194] Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur. J. Pharm., 1983, 93: 21-26

[195] Ohashi E et al. Adenosine N1-oxide exerts anti-inflammatory effects through the PI3K/Akt/GSK-3beta signaling pathway and promotes osteogenic and adipocyte differentiation. Biol. Pharm. Bull., 2019, 42: 968-976

[196] Domazetovic V, Marcucci G, Iantomasi T, Brandi ML, Vincenzini MT. Oxidative stress in bone remodeling: role of antioxidants. Clin. Cases Min. Bone Metab., 2017, 14: 209-216

[197] Chung HY et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev., 2009, 8: 18-30

[198] Duarte, T. L., Talbot, N. P. & Drakesmith, H. NRF2 and hypoxia-inducible factors: key players in the redox control of systemic iron homeostasis. Antioxid. Redox Signal. 35, 433–452 (2021).

[199] Thompson CBInto. Thin air: how we sense and respond to hypoxia. Cell, 2016, 167: 9-11

[200] Ishii T et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem., 2000, 275: 16023-16029

[201] Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol. Med., 2004, 10: 549-557

[202] Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid. Redox Signal., 2006, 8: 76-87

[203] Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol. Rev., 2018, 98: 1169-1203

[204] Hyeon S, Lee H, Yang Y, Jeong W. Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radic. Biol. Med., 2013, 65: 789-799

[205] Chen X et al. Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis. Bone Res., 2021, 9: 15

[206] Jia LL, Xiong YX, Zhang WJ, Ma XN, Xu X. Metformin promotes osteogenic differentiation and protects against oxidative stress-induced damage in periodontal ligament stem cells via activation of the Akt/Nrf2 signaling pathway. Exp. Cell Res., 2020, 386: 12

[207] Guo S et al. Activating AMP-activated protein kinase by an alpha1 selective activator compound 13 attenuates dexamethasone-induced osteoblast cell death. Biochem. Biophys. Res. Commun., 2016, 471: 545-552

[208] Joo MS et al. AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Mol. Cell. Biol., 2016, 36: 1931-1942

[209] Zhan YF et al. Vindoline inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in mice. Front. Pharmacol., 2020, 10: 11

[210] Wu X et al. Pyrroloquinoline quinone prevents testosterone deficiency-induced osteoporosis by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. Am. J. Transl. Res., 2017, 9: 1230-1242

[211] Barzel US, Jowsey J. The effects of chronic acid and alkali administration on bone turnover in adult rats. Clin. Sci., 1969, 36: 517-524

[212] Arnett TR, Dempster DW. Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology, 1986, 119: 119-124

[213] Brandao-Burch A, Utting JC, Orriss IR, Arnett TR. Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization. Calcif. Tissue Int., 2005, 77: 167-174

[214] Blair HC et al. Support of bone mineral deposition by regulation of pH. Am. J. Physiol. Cell Physiol., 2018, 315: C587-c597

[215] Bushinsky DA. Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Am. J. Physiol., 1996, 271: F216-F222

[216] Kohn DH, Sarmadi M, Helman JI, Krebsbach PH. Effects of pH on human bone marrow stromal cells in vitro: implications for tissue engineering of bone. J. Biomed. Mater. Res., 2002, 60: 292-299

[217] Galow AM et al. Increased osteoblast viability at alkaline pH in vitro provides a new perspective on bone regeneration. Biochem. Biophys. Rep., 2017, 10: 17-25

[218] Han SH et al. Acidic pH environments increase the expression of cathepsin B in osteoblasts: the significance of ER stress in bone physiology. Immunopharmacol. Immunotoxicol., 2009, 31: 428-431

[219] Spector JA et al. Osteoblast expression of vascular endothelial growth factor is modulated by the extracellular microenvironment. Am. J. Physiol. Cell Physiol., 2001, 280: C72-C80

[220] Liu W et al. Akermanite used as an alkaline biodegradable implants for the treatment of osteoporotic bone defect. Bioact. Mater., 2016, 1: 151-159

[221] Liu W et al. Spatial distribution of biomaterial microenvironment ph and its modulatory effect on osteoclasts at the early stage of bone defect regeneration. ACS Appl. Mater. Interfaces, 2019, 11: 9557-9572

[222] Ruan C et al. The interfacial pH of acidic degradable polymeric biomaterials and its effects on osteoblast behavior. Sci. Rep., 2017, 7

[223] Sabe VT et al. Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: a review. Eur. J. Med. Chem., 2021, 5: 113705

[224] Liao LX et al. Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy. Proc. Natl. Acad. Sci. USA, 2017, 114: E5986-E5994

[225] Lee JS, Yi JK, An SY, Heo JS. Increased osteogenic differentiation of periodontal ligament stem cells on polydopamine film occurs via activation of integrin and PI3K signaling pathways. Cell. Physiol. Biochem., 2014, 34: 1824-1834

[226] Hanami K et al. Dopamine D2-like receptor signaling suppresses human osteoclastogenesis. Bone, 2013, 56: 1-8

[227] Lee DJ et al. Dopaminergic effects on in vitro osteogenesis. Bone Res., 2015, 3: 15020

[228] Cao L et al. Melatonin mediates osteoblast proliferation through the STIM1/ORAI1 pathway. Front. Pharm., 2022, 13: 851663

[229] Wang X et al. Melatonin promotes bone marrow mesenchymal stem cell osteogenic differentiation and prevents osteoporosis development through modulating circ_0003865 that sponges miR-3653-3p. Stem Cell Res. Ther., 2021, 12: 150

[230] Han Y, Kim YM, Kim HS, Lee KY. Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression. Sci. Rep., 2017, 7

[231] Kim S-S, Jeong S-P, Park B-S, Kim I-R. Melatonin attenuates RANKL-induced osteoclastogenesis via inhibition of Atp6v0d2 and DC-STAMP through MAPK and NFATc1 signaling pathways. Molecules, 2022, 27: 1-13

[232] Xu L et al. Melatonin suppresses estrogen deficiency-induced osteoporosis and promotes osteoblastogenesis by inactivating the NLRP3 inflammasome. Calcif. Tissue Int., 2018, 103: 400-410

[233] Lee S, Le NH, Kang D. Melatonin alleviates oxidative stress-inhibited osteogenesis of human bone marrow-derived mesenchymal stem cells through AMPK activation. Int. J. Med. Sci., 2018, 15: 1083-1091

[234] Du ZH et al. Adenosine A2A receptor mediates inhibition of synovitis and osteoclastogenesis after electroacupuncture in rats with collagen-induced arthritis. Evid.-Based Complement. Altern. Med., 2019, 2019: 11

[235] Kim BH, Oh JH, Lee NK. The inactivation of ERK1/2, p38 and NF-kappa B is involved in the down-regulation of osteoclastogenesis and function by A2B adenosine receptor stimulation. Mol. Cells, 2017, 40: 752-760

[236] Borhani S, Corciulo C, Larranaga-Vera A, Cronstein BN. Signaling at adenosine A2A receptors (A2aR); crosstalk with Wnt/beta-catenin signaling pathway in osteoblasts. Purinergic Signal., 2018, 14: S55-S55

[237] Olkku A, Mahonen A. Wnt and steroid pathways control glutamate signalling by regulating glutamine synthetase activity in osteoblastic cells. Bone, 2008, 43: 483-493

[238] Yuan LQ et al. Taurine transporter is expressed in osteoblasts. Amino Acids, 2006, 31: 157-163

[239] Yuan LQ et al. Taurine inhibits osteoclastogenesis through the taurine transporter. Amino Acids, 2010, 39: 89-99

[240] Kang, I. S. & Kim, C. Taurine 11 Advances in Experimental Medicine and Biology (eds J. Hu et al.) Vol. 1155 p,p. 61–70 (Springer International Publishing Ag, 2019).

[241] Facchini A et al. Role of polyamines in hypertrophy and terminal differentiation of osteoarthritic chondrocytes. Amino Acids, 2012, 42: 667-678

[242] D’Adamo S et al. Spermidine rescues the deregulated autophagic response to oxidative stress of osteoarthritic chondrocytes. Free Radic. Biol. Med., 2020, 153: 159-172

[243] Guidotti S et al. Enhanced osteoblastogenesis of adipose-derived stem cells on spermine delivery via beta-catenin activation. Stem Cells Dev., 2013, 22: 1588-1601

[244] Mandl P et al. Nicotinic acetylcholine receptor ligands inhibit osteoclastogenesis by blocking Rankl-induced calcium-oscillation and induction of Nfatc1 and Cfos. Ann. Rheum. Dis., 2014, 73: A58-A59

[245] Yang Q et al. Betaine alleviates alcohol-induced osteonecrosis of the femoral head via mTOR signaling pathway regulation. Biomed. Pharmacother., 2019, 120: 109486

[246] Santos C et al. Development of hydroxyapatite nanoparticles loaded with folic acid to induce osteoblastic differentiation. Int. J. Pharm., 2017, 516: 185-195

[247] Akpinar A et al. Comparative effects of riboflavin, nicotinamide and folic acid on alveolar bone loss: a morphometric and histopathologic study in rats. Srp. Arh. Celok. Lek., 2016, 144: 273-279

[248] Wu X, Zhou X, Liang S, Zhu X, Dong Z. The mechanism of pyrroloquinoline quinone influencing the fracture healing process of estrogen-deficient mice by inhibiting oxidative stress. Biomed. Pharmacother., 2021, 139: 111598

[249] Hashimoto Y et al. Sphingosine-1-phosphate-enhanced Wnt5a promotes osteogenic differentiation in C3H10T1/2 cells. Cell Biol. Int., 2016, 40: 1129-1136

[250] Ran QC et al. Deferoxamine loaded titania nanotubes substrates regulate osteogenic and angiogenic differentiation of MSCs via activation of HIF-1 alpha signaling. Mat. Sci. Eng. C-Mater., 2018, 91: 44-54

[251] Shi R et al. Electrospun artificial periosteum loaded with DFO contributes to osteogenesis via the TGF-beta1/Smad2 pathway. Biomater. Sci., 2021, 9: 2090-2102

[252] Fan K-J et al. Metformin inhibits inflammation and bone destruction in collagen-induced arthritis in rats. Ann. Transl. Med., 2020, 8: 1565

[253] Gao XL et al. Effects oF Targeted Delivery Of Metformin And Dental Pulp Stem Cells On Osteogenesis Via Demineralized Dentin Matrix Under High Glucose Conditions. ACS Biomater. Sci. Eng., 2020, 6: 2346-2356

[254] Lin JT, Xu RY, Shen X, Jiang HB, Du SH. Metformin promotes the osseointegration of titanium implants under osteoporotic conditions by regulating BMSCs autophagy, and osteogenic differentiation. Biochem. Biophys. Res. Commun., 2020, 531: 228-235

[255] Gu Q, Gu Y, Yang H, Shi Q. Metformin Enhances Osteogenesis And Suppresses Adipogenesis Of Human Chorionic Villous Mesenchymal Stem Cells. Tohoku J. Exp. Med., 2017, 241: 13-19

[256] Marycz K et al. Metformin decreases reactive oxygen species, enhances osteogenic properties of adipose-derived multipotent mesenchymal stem cells in vitro, and increases bone density in vivo. Oxid. Med. Cell Longev., 2016, 2016: 9785890

[257] Bahrambeigi S, Yousefi B, Rahimi M, Shafiei-Irannejad V. Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomed. Pharmacother., 2019, 109: 1593-1601

[258] Liu Z et al. The effects of tranylcypromine on osteoclastogenesis in vitro and in vivo. FASEB J., 2019, 33: 9828-9841

[259] LaBranche TP et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum., 2012, 64: 3531-3542

[260] Yannaki E et al. The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats. Arthritis Rheum., 2010, 62: 3277-3288

[261] Pennypacker BL et al. Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model. J. Orthop. Res., 2016, 34: 72-80

[262] Khosla S. Odanacatib: location and timing are everything. J. Bone Min. Res., 2012, 27: 506-508

[263] Hao L et al. A small molecule, odanacatib, inhibits inflammation and bone loss caused by endodontic disease. Infect. Immun., 2015, 83: 1235-1245

[264] Wang Y, Fu Q, Zhao W. Tetramethylpyrazine inhibits osteosarcoma cell proliferation via downregulation of NF-kappaB in vitro and in vivo. Mol. Med. Rep., 2013, 8: 984-988

[265] Jia X et al. Berberine ameliorates periodontal bone loss by regulating gut microbiota. J. Dent. Res., 2019, 98: 107-116

[266] Liu M, Xu Z. Berberine promotes the proliferation and osteogenic differentiation of alveolar osteoblasts through regulating the expression of miR-214. Pharmacology, 2021, 106: 70-78

[267] Fukuma Y et al. Rutaecarpine attenuates osteoclastogenesis by impairing macrophage colony stimulating factor and receptor activator of nuclear factor -B ligand-stimulated signalling pathways. Clin. Exp. Pharmacol. Physiol., 2018, 45: 863-865

[268] Chen S et al. Lycorine suppresses RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced osteoporosis and titanium particle-induced osteolysis in vivo. Sci. Rep., 2015, 5

[269] Park HJ, Gholam-Zadeh M, Suh JH, Choi HS. Lycorine attenuates autophagy in osteoclasts via an axis of mROS/TRPML1/TFEB to Reduce LPS-induced bone loss. Oxid. Med. Cell. Longev., 2019, 2019: 11

[270] He LG et al. Sinomenine induces apoptosis in RAW 264.7 cell-derived osteoclasts in vitro via caspase-3 activation. Acta Pharmacol. Sin., 2014, 35: 203-210

[271] He LG et al. Sinomenine down-regulates TLR4/TRAF6 expression and attenuates lipopolysaccharide-induced osteoclastogenesis and osteolysis. Eur. J. Pharmacol., 2016, 779: 66-79

[272] Zhang YY et al. Sinomenine inhibits osteolysis in breast cancer by reducing IL-8/CXCR1 and c-Fos/NFATc1 signaling. Pharmacol. Res., 2019, 142: 140-150

[273] Zheng T, Noh A, Park H, Yim M. Aminocoumarins inhibit osteoclast differentiation and bone resorption via downregulation of nuclear factor of activated T cells c1. Biochem. Pharmacol., 2013, 85: 417-425

[274] Clough BH et al. Theobromine upregulates osteogenesis by human mesenchymal stem cells in vitro and accelerates bone development in rats. Calcif. Tissue Int., 2017, 100: 298-310

[275] Yuan FL et al. Leonurine hydrochloride inhibits osteoclastogenesis and prevents osteoporosis associated with estrogen deficiency by inhibiting the NF-kappaB and PI3K/Akt signaling pathways. Bone, 2015, 75: 128-137

[276] Yonezawa T et al. Harmine, a beta-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo. Eur. J. Pharmacol., 2011, 650: 511-518

[277] Chen X et al. Matrine derivate MASM uncovers a novel function for ribosomal protein S5 in osteoclastogenesis and postmenopausal osteoporosis. Cell Death Dis., 2017, 8

[278] Xin Z et al. A matrine derivative M54 suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by targeting ribosomal protein S5. Front. Pharm., 2018, 9: 22

[279] Li J et al. Matrine enhances osteogenic differentiation of bone marrow-derived mesenchymal stem cells and promotes bone regeneration in rapid maxillary expansion. Arch. Oral. Biol., 2020, 118: 104862

[280] Kwak SC et al. Securinine suppresses osteoclastogenesis and ameliorates inflammatory bone loss. Phytother. Res., 2020, 34: 3029-3040

[281] Sun Z et al. Magnoflorine suppresses MAPK and NF-kappaB signaling to prevent inflammatory osteolysis induced by titanium particles in vivo and osteoclastogenesis via RANKL in vitro. Front. Pharm., 2020, 11: 389

[282] Liu Q et al. Nitidine chloride prevents OVX-induced bone loss via suppressing NFATc1-mediated osteoclast differentiation. Sci. Rep., 2016, 6

[283] Bowers A et al. Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor. J. Am. Chem. Soc., 2008, 130: 11219-11222

[284] Lee SU et al. In vitro and in vivo osteogenic activity of largazole. ACS Med. Chem. Lett., 2011, 2: 248-251

[285] Farina C, Gagliardi S. Selective inhibition of osteoclast vacuolar H(+)-ATPase. Curr. Pharm. Des., 2002, 8: 2033-2048

[286] Niikura K, Takeshita N, Takano M. A vacuolar ATPase inhibitor, FR167356, prevents bone resorption in ovariectomized rats with high potency and specificity: potential for clinical application. J. Bone Min. Res., 2005, 20: 1579-1588

[287] Niikura K, Takeshita N, Chida N. A novel inhibitor of vacuolar ATPase, FR202126, prevents alveolar bone destruction in experimental periodontitis in rats. J. Toxicol. Sci., 2005, 30: 297-304

[288] Niikura K. Comparative analysis of the effects of a novel vacuolar adenosine 5’-triphosphatase inhibitor, FR202126, and doxycycline on bone loss caused by experimental periodontitis in rats. J. Periodontol., 2006, 77: 1211-1216

[289] Niikura K, Nakajima S, Takano M, Yamazaki H. FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats. Bone, 2007, 40: 888-894

[290] Liou SF et al. KMUP-1 promotes osteoblast differentiation through cAMP and cGMP pathways and signaling of BMP-2/Smad1/5/8 and Wnt/beta-catenin. J. Cell Physiol., 2015, 230: 2038-2048

[291] Yuan Y et al. Fumitremorgin C attenuates osteoclast formation and function via suppressing RANKL-induced signaling pathways. Front. Pharm., 2020, 11: 238

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82030067, 82161160342)

Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)(2020A1515111190)

Shenzhen Fundamental Research Foundation [Grant No.JCYJ20210324113001005]; Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties [Grant No. NO.SZGSP001]

Shenzhen Fundamental Research Foundation [Grant No. JCYJ20190812162809131, JCYJ20200109114006014]

Youth Innovation Promotion Association of the Chinese Academy of Sciences (Youth Innovation Promotion Association CAS)(2019350)

National Key R&D Program [Grant No. 2018YFA0703100]; Shenzhen Fundamental Research Foundation [Grant No. JCYJ20210324115814040]