Sialin-STAT3 axis regulates bone homeostasis in mice

Abstract

Mitochondrial regulation in mesenchymal stem cells (MSCs) serves as a critical determinant of bone formation and skeletal homeostasis. While dietary nitrate and its transporter Sialin are implicated in systemic homeostasis, their specific roles in MSCs' function remain unclear. Here, we demonstrate that Sialin deficiency impairs MSCs' function and disrupts bone homeostasis. Gain- and loss-of-function studies reveal that Sialin localizes to the mitochondrial membrane and promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity. Mechanistically, Sialin recruits pSTAT3^S727 to mitochondria, forming a functional complex that activates mitochondrial bioenergy and stabilizes bone remodeling. Notably, dietary nitrate restores Sialin expression in aged mice, thereby enhancing MSCs' function and preventing osteoporosis. Our findings identify a nutrient-responsive signaling axis—nitrate-Sialin-pSTAT3^S727—that promotes osteogenic differentiation via mitochondrial homeostasis, offering a potential therapeutic strategy for age-related osteoporosis.

References

[1] Dalle CLet al.. The bone microenvironment: new insights into the role of stem cells and cell communication in bone regeneration. Stem. Cell. Res. Ther., 2025, 16: 169

[2] Sharma Get al.. Epigenetic regulation of bone remodeling and bone metastasis. Semin. Cell. Dev. Biol., 2024, 154: 275-285

[3] Bolamperti S, Villa I, Rubinacci A. Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Res., 2022, 10: 48

[4] Pignolo RJ, Law SF, Chandra A. Bone aging, cellular senescence, and Osteoporosis. JBMR Plus, 2021, 5: e10488

[5] Bartl R, Bartl C. Current prevention and treatment strategies for osteoporosis. Fracture-oriented, effective, low side effects and inexpensive. Internist, 2015, 56: 1445-1457

[6] Zhou Ret al.. Endocrine role of bone in the regulation of energy metabolism. Bone Res., 2021, 9: 25

[7] Bertels JC, He G, Long F. Metabolic reprogramming in skeletal cell differentiation. Bone Res., 2024, 12: 57

[8] Bahat A, Gross A. Mitochondrial plasticity in cell fate regulation. J. Biol. Chem., 2019, 294: 13852-13863

[9] Liu Y, Wang L, Ai J, Li K. Mitochondria in mesenchymal stem cells: key to fate determination and therapeutic potential. Stem. Cell. Rev. Rep., 2024, 20: 617-636

[10] Yan W, Diao S, Fan Z. The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells. Stem. Cell. Res. Ther., 2021, 12: 140

[11] Zong Yet al.. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal. Transduct. Target. Ther., 2024, 9: 124

[12] Wen Het al.. Mitochondrial diseases: from molecular mechanisms to therapeutic advances. Signal. Transduct. Target. Ther., 2025, 10: 9

[13] Chakrabarty RP, Chandel NS. Beyond ATP, new roles of mitochondria. Biochem, 2022, 44: 2-8

[14] Chakrabarty RP, Chandel NS. Mitochondria as signaling organelles control mammalian stem cell fate. Cell. Stem. Cell., 2021, 28: 394-408

[15] Li X, Jiang O, Wang S. Molecular mechanisms of cellular metabolic homeostasis in stem cells. Int. J. Oral. Sci., 2023, 15: 52

[16] Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal. Transduct. Target. Ther., 2023, 8: 333

[17] Liu Het al.. Energy metabolism in health and diseases. Signal. Transduct. Target. Ther., 2025, 10: 69

[18] Qin L, Wang S. Protective roles of inorganic nitrate in health and diseases. Curr. Med., 2022, 1: 1-13

[19] Lundberg J, Weitzberg E, Gladwin M. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug. Discov., 2008, 7: 156-167

[20] Qin Let al.. Sialin (SLC17A5) Functions as a nitrate transporter in the plasma membrane. Proc. Natl. Acad. Sci. USA., 2012, 109: 13434-13439

[21] Zhou J, Pan W, Li X, Wang S. The important role of the inorganic nitrate cycle mediated by the oral salivary glands in systemic health (in Chinese). Chin. Sci. Bull., 2023, 68: 1-11

[22] Wang Wet al.. Total body irradiation-induced colon damage is prevented by nitrate-mediated suppression of oxidative stress and homeostasis of the gut microbiome. Nitric Oxide, 2020, 102: 1-11

[23] Pan Wet al.. Nanonitrator: novel enhancer of inorganic nitrate’s protective effects, predicated on swarm learning approach. Sci. Bull., 2023, 68: 838-850

[24] Li Xet al.. Salivary nitrate prevents osteoporosis via regulating bone marrow mesenchymal stem cells proliferation and differentiation. J. Orthop. Transl., 2024, 45: 188-196

[25] Larsen Fet al.. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell. Metab., 2011, 13: 149-159

[26] Omar S, Webb A, Lundberg J, Weitzberg E. Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases. J. Intern. Med., 2016, 279: 315-336

[27] Li Set al.. Inorganic nitrate alleviates irradiation-induced salivary gland damage by inhibiting pyroptosis. Free. Radic. Biol. Med., 2021, 175: 130-140

[28] Gao Zet al.. Hierarchical graph learning for protein–protein interaction. Nat. Commun., 2023, 14: 1093-1105

[29] Wegrzyn Jet al.. Function of mitochondrial Stat3 in cellular respiration. Science, 2009, 323: 793-797

[30] Yang Yet al.. STAT3 controls osteoclast differentiation and bone homeostasis by regulating NFATc1 transcription. J. Biol. Chem., 2019, 294: 15395-15407

[31] Hou X, Tian F. STAT3-mediated osteogenesis and osteoclastogenesis in osteoporosis. Cell. Commun. Signal., 2022, 20 112

[32] Zhou Set al.. STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis. Nat. Commun., 2021, 12: 6891-6908

[33] Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J. Clin. Invest., 2005, 115: 3318-3325

[34] Rogers M, Crockett J, Coxon F, Monkkonen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone, 2011, 49: 34-41

[35] Suzuki T, Nakamura Y, Kato H. Changes of bone-related minerals during denosumab administration in post-menopausal osteoporotic patients. Nutrients, 2017, 9: 871-880

[36] Wang W, Gallo L, Jadhav A, Hawkins R, Parker C. The druggability of solute carriers. J. Med. Chem., 2020, 63: 3834-3867

[37] Hu Wet al.. The molecular mechanism of sialic acid transport mediated by Sialin. Sci. Adv., 2023, 9 eade8346

[38] Ito K. Metabolism and the control of cell fate decisions and stem cell renewal. Annu. Rev. Cell. Dev. Bi., 2016, 32: 399-409

[39] Carbognin E, Betto R, Soriano M, Smith A, Martello G. Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency. Embo. J., 2016, 35: 618-634

[40] Szczepanek Ket al.. Mitochondrial-targeted signal transducer and activator of transcription 3 (Stat3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species. J. Biol. Chem., 2011, 286: 29610-29620

[41] Luo Xet al.. Enhanced transcriptional activity and mitochondrial localization of Stat3 co-induce axon regrowth in the adult central nervous system. Cell. Rep., 2016, 15: 398-410

[42] Gough Det al.. Mitochondrial STAT3 supports ras-dependent oncogenic transformation. Science, 2009, 324: 1713-1716

[43] Sarafian Tet al.. Disruption of astrocyte STAT3 signaling decreases mitochondrial function and increases oxidative stress in vitro. PLoS One, 2010, 5 e9532

[44] Duncan Cet al.. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat. Med., 1995, 1: 546-551

[45] Wang Het al.. Inorganic nitrate alleviates the senescence-related decline in liver function. Sci. China Life. Sci., 2018, 61: 24-34

[46] Gheibi Set al.. Nitrite increases glucose-stimulated insulin secretion and islet insulin content in obese type 2 diabetic male rats. Nitric Oxide, 2017, 64: 39-51

[47] Khalifi S, Rahimipour A, Jeddi S, Ghanbari M, Ghasemi A. Dietary nitrate improves glucose tolerance and lipid profile in an animal model of hyperglycemia. Nitric Oxide, 2015, 44: 24-30

[48] Ma Let al.. Rebalancing glucolipid metabolism and gut microbiome dysbiosis by nitrate-dependent alleviation of high-fat diet-induced obesity. Bmj. Open. Diab Res. Care., 2020, 8 e001255

[49] Bouxsein MLet al.. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J. Bone Miner. Res., 2010, 25: 1468-1486

[50] Cao Het al.. Activating transcription factor 4 regulates osteoclast differentiation in mice. J. Clin. Invest., 2010, 120: 2755-2766

Funding

the Beijing Municipal Government grant (Beijing Laboratory of Oral Health, PXM2021_014226_000041 and PXM2021_014226_000020; Beijing Scholar Program-PXM2018_014226_000021), the National Natural Science Foundation of China (82030031, 82350003 and 92149301), Chinese Research Unit of Tooth Development and Regeneration, Academy of Medical Sciences (No. 2019-12M-5-031).

the National Natural Science Foundation of China (82401082), the State Key Laboratory of Oral Diseases Open Fund (SKLOD2023OF11), Young Scientist Program of Beijing Stomatological Hospital, Capital Medical University (YSP202308).

RIGHTS & PERMISSIONS

The Author(s)