Estradiol regulates osteoclast sialylation via ST3Gal1 in postmenopausal osteoporosis

Abstract

Estrogen deficiency after menopause accelerates bone loss by stimulating osteoclast formation and activity, but the molecular pathways that link estrogen signaling to osteoclast regulation remain incompletely defined. Here, we identify the sialyltransferase ST3GAL-I as a key mediator of RANKL-induced osteoclastogenesis. RANKL activates c-FOS to drive ST3GAL1 transcription, whereas estrogen-bound ERα competes with TRAF6 and suppresses this c-FOS–dependent induction. In a clinical cohort of pre-menopausal and post-menopausal women with or without osteoporosis, serum total and α-2,3-linked sialic acid levels increased with age and were highest in post-menopausal osteoporotic patients. Single-cell RNA sequencing of human bone revealed that osteoclasts form a prominent cluster only after menopause, where FOS, CTSK, and ST3GAL1 are strongly co-expressed, and the estrogen-responsive gene PGR is down-regulated. Additionally, in vivo experiments showed that sialidase treatment in estrogen-deficient models effectively reduced osteoclast-mediated bone loss, mimicking the effects of estradiol. These findings define a direct molecular link between loss of estrogen and activation of a FOS–ST3GAL1 sialylation pathway in osteoclasts, providing mechanistic insight into the enhanced bone resorption characteristic of post-menopausal osteoporosis.

References

[1] Lips P, van Schoor NM. Quality of life in patients with osteoporosis. Osteoporos. Int., 2005, 16: 447-455

[2] Eastell Ret al.. Postmenopausal osteoporosis. Nat. Rev. Dis. Prim., 2016, 2 16069

[3] van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone, 2001, 29: 517-522

[4] Clowes JA, Riggs BL, Khosla S. The role of the immune system in the pathophysiology of osteoporosis. Immunol. Rev., 2005, 208: 207-227

[5] Manolagas SC, O’Brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat. Rev. Endocrinol., 2013, 9: 699-712

[6] Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J. Bone Miner. Res., 1996, 11: 337-349

[7] Lacey DLet al.. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 1998, 93: 165-176

[8] Yasuda Het al.. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA, 1998, 95: 3597-3602

[9] Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA, 2004, 292: 490-495

[10] Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J. Clin. Invest., 2006, 116: 1186-1194

[11] Eghbali-Fatourechi Get al.. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Invest., 2003, 111: 1221-1230

[12] Shevde NK, Bendixen AC, Dienger KM, Pike JW. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc. Natl. Acad. Sci. USA, 2000, 97: 7829-7834

[13] Kameda Tet al.. Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. J. Exp. Med., 1997, 186: 489-495

[14] Stanczyk FZ, Clarke NJ. Measurement of estradiol-challenges ahead. J. Clin. Endocrinol. Metab., 2014, 99: 56-58

[15] Varki A. Sialic acids in human health and disease. Trends Mol. Med., 2008, 14: 351-360

[16] Crean SMet al.. N-linked sialyated sugar receptors support haematopoietic cell-osteoblast adhesions. Br. J. Haematol., 2004, 124: 534-546

[17] Keppler OTet al.. Differential sialylation of cell surface glycoconjugates in a human B lymphoma cell line regulates susceptibility for CD95 (APO-1/Fas)-mediated apoptosis and for infection by a lymphotropic virus. Glycobiology, 1999, 9: 557-569

[18] Stamatos NM, Curreli S, Zella D, Cross AS. Desialylation of glycoconjugates on the surface of monocytes activates the extracellular signal-related kinases ERK 1/2 and results in enhanced production of specific cytokines. J. Leukoc. Biol., 2004, 75: 307-313

[19] Olaru OG, Constantin GI, Pena CM. Variation of total serum sialic acid concentration in postmenopausal women. Exp. Ther. Med., 2020, 20: 2455-2459

[20] Takahata Met al.. Sialylation of cell surface glycoconjugates is essential for osteoclastogenesis. Bone, 2007, 41: 77-86

[21] Valimaki VVet al.. Serum estradiol, testosterone, and sex hormone-binding globulin as regulators of peak bone mass and bone turnover rate in young Finnish men. J. Clin. Endocrinol. Metab., 2004, 89: 3785-3789

[22] Wang Yet al.. Studies and application of sialylated milk components on regulating neonatal gut microbiota and health. Front. Nutr., 2021, 8 766606

[23] Robinson LJet al.. Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-alpha with BCAR1 and Traf6. Exp. Cell Res., 2009, 315: 1287-1301

[24] Li F, Ding J. Sialylation is involved in cell fate decision during development, reprogramming and cancer progression. Protein Cell, 2019, 10: 550-565

[25] Ota I, Ota Y, Ota K, Eda H, Ohta H. TRACP-5b/BAP score after 3 months of treatment with combined SERM/E2 therapy can predict changes in lumbar spine bone mineral density after 1 year of treatment in early postmenopausal osteopenia. JBMR Plus, 2022, 6: e10690

[26] Engdahl Cet al.. Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Res. Ther., 2018, 20: 84

[27] Harre Uet al.. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat. Commun., 2015, 6 6651

[28] Sehic Eet al.. Immunoglobulin G complexes without sialic acids enhance osteoclastogenesis but do not affect arthritis-mediated bone loss. Scand. J. Immunol., 2021, 93 e13009

[29] Ishida-Kitagawa Net al.. Siglec-15 protein regulates formation of functional osteoclasts in concert with DNAX-activating protein of 12 kDa (DAP12). J. Biol. Chem., 2012, 287: 17493-17502

[30] Dou Cet al.. Sialylation of TLR2 initiates osteoclast fusion. Bone Res., 2022, 10: 24

[31] Maverakis Eet al.. Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review. J. Autoimmun., 2015, 57: 1-13

[32] Zhou Xet al.. Antibody glycosylation in autoimmune diseases. Autoimmun. Rev., 2021, 20 102804

[33] Perdicchio Met al.. Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells. Proc. Natl. Acad. Sci. USA, 2016, 113: 3329-3334

[34] Li Wet al.. Investigation of the potential use of sialic acid as a biomarker for rheumatoid arthritis. Ann. Clin. Lab Sci., 2019, 49: 224-231

[35] Wang Yet al.. Loss of alpha2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis. Nat. Commun., 2021, 12 2343

[36] Varki A, Gagneux P. Multifarious roles of sialic acids in immunity. Ann. N. Y. Acad. Sci., 2012, 1253: 16-36

[37] Vattepu R, Sneed SL, Anthony RM. Sialylation as an important regulator of antibody function. Front. Immunol., 2022, 13: 818736

[38] Zhu W, Zhou Y, Guo L, Feng S. Biological function of sialic acid and sialylation in human health and disease. Cell Death Discov., 2024, 10: 415

[39] Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat. Rev. Immunol., 2007, 7: 255-266

[40] Lubbers J, Rodriguez E, van Kooyk Y. Modulation of immune tolerance via siglec-sialic acid interactions. Front. Immunol., 2018, 9: 2807

[41] Pillai S, Netravali IA, Cariappa A, Mattoo H. Siglecs and immune regulation. Annu. Rev. Immunol., 2012, 30: 357-392

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82172489)

RIGHTS & PERMISSIONS

The Author(s)