Volume 6,Issue 4
Molecular Mechanisms of Osteoclast Precursor Fusion: From DC-STAMP to Novel Regulatory Proteins
Osteoclasts are multinucleated giant cells responsible for bone resorption in the skeletal system. Osteoclast precursors originate from monocytes and macrophages, as well as dendritic cells. Their multinucleation process is crucial for maintaining bone homeostasis. Studies indicate that efficient fusion of mononuclear precursor cells is a prerequisite for forming fully functional multinucleated osteoclasts. This unique cell fusion capability allows osteoclasts to form large, multinucleated cells with enhanced bone resorptive capacity. Under physiological conditions, a precisely regulated fusion process generates multinucleated osteoclasts of predictable size, with the number of nuclei positively correlating with bone resorption activity. Notably, each fusion event significantly increases the bone resorptive activity of osteoclasts, a characteristic vital for lifelong bone remodeling processes.
[1] Søe K, Delaisse JM, Borggaard XG, 2021, Osteoclast Formation at the Bone Marrow/Bone Surface Interface: Importance of Structural Elements, Matrix, and Intercellular Communication. Seminars in Cell & Developmental Biology, 112: 8–15.
[2] Chen EH, Grote E, Mohler W, et al., 2007, Cell-Cell Fusion. FEBS Letters, 581: 2181–2193.
[3] Xing L, Xiu Y, Boyce BF, 2012, Osteoclast Fusion and Regulation by RANKL-Dependent and Independent Factors. World Journal of Orthopedics, 3: 212–222.
[4] Kim K, Lee SH, Ha KJ, et al., 2008, NFATc1 Induces Osteoclast Fusion via Up-Regulation of Atp6v0d2 and the Dendritic Cell-Specific Transmembrane Protein (DC-STAMP). Molecular Endocrinology (Baltimore, Md.), 22: 176–185.
[5] Ishii M, Saeki Y, 2008, Osteoclast Cell Fusion: Mechanisms and Molecules. Modern Rheumatology, 18: 220–227.
[6] Krishnacoumar B, Stenzel M, Garibagaoglu H, et al., 2024, Caspase-8 Promotes Scramblase-Mediated Phosphatidylserine Exposure and Fusion of Osteoclast Precursors. Bone Research, 12: 40.
[7] Barnea-Zohar M, Stein M, Reuven N, et al., 2024, SNX10 Regulates Osteoclastogenic Cell Fusion and Osteoclast Size in Mice. J Bone Miner Res, 39: 1503–1517.
[8] Leikina E, Whitlock JM, Melikov K, et al., 2024, Formation of Multinucleated Osteoclasts Depends on an Oxidized Species of Cell Surface-Associated La Protein. eLife, 13.
[9] Gu R, Liu H, Hu M, et al., 2023, D-Mannose Prevents Bone Loss under Weightlessness. Journal of Translational Medicine, 21: 8.
[10] Wan Y, Nemoto YL, Oikawa T, et al., 2025, Mechanical Control of Osteoclast Fusion by Membrane-Cortex Attachment and BAR Proteins. The Journal of Cell Biology, 224.
[11] Whitlock JM, Leikina E, Melikov K, et al., 2023, Cell Surface-Bound La Protein Regulates the Cell Fusion Stage of Osteoclastogenesis. Nature Communications, 14: 616.
[12] Garcia-Hernandez ML, Rangel-Moreno J, Garcia-Castaneda M, et al., 2022, Dendritic Cell-Specific Transmembrane Protein Is Required for Synovitis and Bone Resorption in Inflammatory Arthritis. Front Immunol, 13: 1026574.
[13] Wang Q, Wang H, Yan H, et al., 2022, Suppression of Osteoclast Multinucleation via a Posttranscriptional Regulation-Based Spatiotemporally Selective Delivery System. Science Advances, 8: eabn3333.
[14] Kong X, Liu H, Chen S, et al., 2025, Bioengineered Bacterial Extracellular Vesicles for Targeted Delivery of an Osteoclastogenesis-Inhibitory Peptide to Alleviate Osteoporosis. Journal of Controlled Release: Official Journal of the Controlled Release Society, 382: 113751.
[15] Wang Q, Xie J, Zhou C, et al., 2022, Substrate Stiffness Regulates the Differentiation Profile and Functions of Osteoclasts via Cytoskeletal Arrangement. Cell Proliferation, 55: e13172.
[16] Li X, Jiang Y, Liu X, et al., 2023, Mesenchymal Stem Cell-Derived Apoptotic Bodies Alleviate Alveolar Bone Destruction by Regulating Osteoclast Differentiation and Function. International Journal of Oral Science, 15: 51.
[17] Yagi M, Miyamoto T, Sawatani Y, et al., 2005, DC-STAMP Is Essential for Cell-Cell Fusion in Osteoclasts and Foreign Body Giant Cells. The Journal of Experimental Medicine, 202: 345–351.
[18] Jansen BJ, Eleveld-Trancikova D, Sanecka A, et al., 2009, OS9 Interacts with DC-STAMP and Modulates Its Intracellular Localization in Response to TLR Ligation. Molecular Immunology, 46: 505–515.
[19] Moura SR, Sousa AB, Olesen JB, et al., 2024, Stage-Specific Modulation of Multinucleation, Fusion, and Resorption by the Long Non-Coding RNA DLEU1 and miR-16 in Human Primary Osteoclasts. Cell Death & Disease, 15: 741.
[20] van Duijn A, Van der Burg SH, Scheeren FA, 2022, CD47/SIRPα Axis: Bridging Innate and Adaptive Immunity. Journal for Immunotherapy of Cancer, 10.
[21] Chiu YH, Schwarz E, Li D, et al., 2017, Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) Regulates Osteoclast Differentiation via the Ca(2+)/NFATc1 Axis. Journal of Cellular Physiology, 232: 2538–2549.
[22] Kim SC, Gu DR, Yang H, et al., 2025, Polysaccharides from Psoralea Corylifolia Seeds Suppress Osteoclastogenesis and Alleviate Osteoporosis. International Journal of Biological Macromolecules, 315: 144423.
[23] Liu T, Jiang L, Xiang Z, et al., 2022, Tereticornate A Suppresses RANKL-Induced Osteoclastogenesis via the Downregulation of c-Src and TRAF6 and the Inhibition of RANK Signaling Pathways. Biomedicine & Pharmacotherapy, 151: 113140.
[24] Zhu G, Chen W, Tang CY, et al., 2022, Knockout and Double Knockout of Cathepsin K and Mmp9 Reveals a Novel Function of Cathepsin K as a Regulator of Osteoclast Gene Expression and Bone Homeostasis. International Journal of Biological Sciences, 18: 5522–5538.
[25] Xu W, Chao R, Xie X, et al., 2024, IL13Ralpha2 as a Crucial Receptor for Chi3l1 in Osteoclast Differentiation and Bone Resorption through the MAPK/AKT Pathway. Cell Communication and Signaling: CCS, 22: 81.
[26] Sviercz FA, Jarmoluk P, Cevallos CG, et al., 2023, Massively HIV-1-Infected Macrophages Exhibit a Severely Hampered Ability to Differentiate into Osteoclasts. Front Immunol, 14: 1206099.
[27] Li Y, Yang JY, Lin ML, et al., 2025, ACT001 Improves OVX-Induced Osteoporosis by Suppressing the NF-kappaB/NLRP3 Signaling Pathway. Molecular Medicine (Cambridge, Mass.), 31: 131.
[28] Qu T, Li B, Wang Y, 2022, Targeting CD47/SIRPalpha as a Therapeutic Strategy, Where We Are and Where We Are Headed. Biomarker Research, 10: 20.
[29] Chen F, Tian L, Pu X, et al., 2022, Enhanced Ectopic Bone Formation by Strontium-Substituted Calcium Phosphate Ceramics through Regulation of Osteoclastogenesis and Osteoblastogenesis. Biomaterials Science, 10: 5925–5937.
[30] Sviercz F, Jarmoluk P, Godoy Coto J, et al., 2024, The Abortive SARS-CoV-2 Infection of Osteoclast Precursors Promotes Their Differentiation into Osteoclasts. Journal of Medical Virology, 96: e29597.
[31] Wolin SL, Cedervall T, 2002, The La Protein. Annual Review of Biochemistry, 71: 375–403.
[32] Sims NA, Walsh NC, 2012, Intercellular Cross-Talk among Bone Cells: New Factors and Pathways. Current Osteoporosis Reports, 10: 109–117.
[33] van Duijn A, Van der Burg SH, Scheeren FA, 2022, CD47/SIRPα Axis: Bridging Innate and Adaptive Immunity. Journal for Immunotherapy of Cancer, 10.
[34] Zheng J, He W, Chen Y, et al., 2025, Erianin Serves as an NFATc1 Inhibitor to Prevent Breast Cancer-Induced Osteoclastogenesis and Bone Destruction. Journal of Advanced Research, 69: 399–411.
[35] Logtenberg MEW, Scheeren FA, Schumacher TN, 2020, The CD47-SIRPα Immune Checkpoint. Immunity, 52: 742–752.
[36] Zhu D, Hadjivassiliou H, Jennings C, et al., 2024, CC-96673 (BMS-986358), an Affinity-Tuned Anti-CD47 and CD20 Bispecific Antibody with Fully Functional Fc, Selectively Targets and Depletes Non-Hodgkin's Lymphoma. mAbs, 16: 2310248.
[37] Xu Y, Song D, Lin X, et al., 2023, Corylifol A Protects against Ovariectomized-Induced Bone Loss and Attenuates RANKL-Induced Osteoclastogenesis via ROS Reduction, ERK Inhibition, and NFATc1 Activation. Free Radical Biology & Medicine, 196: 121–132.
[38] van Helden MJ, Zwarthoff SA, Arends RJ, et al., 2023, BYON4228 Is a Pan-Allelic Antagonistic SIRPalpha Antibody That Potentiates Destruction of Antibody-Opsonized Tumor Cells and Lacks Binding to SIRPgamma on T Cells. Journal for Immunotherapy of Cancer, 11: 1–12.
[39] Cendrowicz E, Jacob L, Greenwald S, et al., 2022, DSP107 Combines Inhibition of CD47/SIRPalpha Axis With Activation of 4-1BB to Trigger Anticancer Immunity. Journal of Experimental & Clinical Cancer Research: CR, 41: 97.
[40] Bae S, Kim K, Kang K, et al., 2023, RANKL-Responsive Epigenetic Mechanism Reprograms Macrophages Into Bone-Resorbing Osteoclasts. Cellular & Molecular Immunology, 20: 94–109.
[41] Sheng M, Lin Y, Xu D, et al., 2021, CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation. Hepatology (Baltimore, Md.), 74: 1560–1577.
[42] Han X, Sterling H, Chen Y, et al., 2000, CD47, a Ligand for the Macrophage Fusion Receptor, Participates in Macrophage Multinucleation. The Journal of Biological Chemistry, 275: 37984–37992.
[43] Maile LA, DeMambro VE, Wai C, et al., 2011, An Essential Role for the Association of CD47 to SHPS-1 in Skeletal Remodeling. Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research, 26: 2068–2081.
[44] Uluçkan O, Becker SN, Deng H, et al., 2009, CD47 Regulates Bone Mass and Tumor Metastasis to Bone. Cancer Research, 69: 3196–3204.
[45] Lundberg P, Koskinen C, Baldock PA, et al., 2007, Osteoclast Formation Is Strongly Reduced Both in Vivo and in Vitro in the Absence of CD47/SIRPalpha-Interaction. Biochemical and Biophysical Research Communications, 352: 444–448.
[46] Møller AM, Delaissé JM, Søe K, 2017, Osteoclast Fusion: Time-Lapse Reveals Involvement of CD47 and Syncytin-1 at Different Stages of Nuclearity. Journal of Cellular Physiology, 232: 1396–1403.
[47] Hobolt-Pedersen AS, Delaissé JM, Søe K, 2014, Osteoclast Fusion Is Based on Heterogeneity Between Fusion Partners. Calcif Tissue Int, 95: 73–82.
[48] Zheng H, Liu Y, Deng Y, et al., 2024, Recent Advances of NFATc1 in Rheumatoid Arthritis-Related Bone Destruction: Mechanisms and Potential Therapeutic Targets. Molecular Medicine (Cambridge, Mass.), 30: 20.
[49] Che Z, Wang W, Zhang L, et al., 2025, Therapeutic Strategies Targeting CD47-SIRPalpha Signaling Pathway in Gastrointestinal Cancers Treatment. Journal of Pharmaceutical Analysis, 15: 101099.
[50] Biedermann A, Patra-Kneuer M, Mougiakakos D, et al., 2024, Blockade of the CD47/SIRPalpha Checkpoint Axis Potentiates the Macrophage-Mediated Antitumor Efficacy of Tafasitamab. Haematologica, 109: 3928–3940.
[51] Luo N, Zhang L, Xiu C, et al., 2024, Piperlongumine, a Piper Longum-Derived Amide Alkaloid, Protects Mice From Ovariectomy-Induced Osteoporosis by Inhibiting Osteoclastogenesis via Suppression of p38 and JNK Signaling. Food & Function, 15: 2154–2169.
[52] Gal M, Kim O, Tran PT, et al., 2022, Mussaendoside O, a N-Triterpene Cycloartane Saponin, Attenuates RANKL-Induced Osteoclastogenesis and Inhibits Lipopolysaccharide-Induced Bone Loss. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 105: 154378.
[53] Groetsch B, Schachtschabel E, Tripal P, et al., 2022, Inflammatory Activation of the FcgammaR and IFNgammaR Pathways Co-Influences the Differentiation and Activity of Osteoclasts. Front Immunol, 13: 958974.
[54] Kim H, Takegahara N, Choi Y, 2023, IgSF11-Mediated Phosphorylation of Pyruvate Kinase M2 Regulates Osteoclast Differentiation and Prevents Pathological Bone Loss. Bone Research, 11: 17.
[55] Dou C, Zhen G, Dan Y, et al., 2022, Sialylation of TLR2 Initiates Osteoclast Fusion. Bone Research, 10: 24.
[56] Leikina E, Tsaturyan AK, Melikov K, et al., 2025, Phosphatidylserine Exposure and Extracellular Annexin A5 Weaken the Actin Cortex in Osteoclast Fusion. bioRxiv: The Preprint Server for Biology, 1–12.
[57] Li YN, Chen CW, Trinh-Minh T, et al., 2022, Dynamic Changes in O-GlcNAcylation Regulate Osteoclast Differentiation and Bone Loss via Nucleoporin 153. Bone Research, 10: 51.
[58] Kim H, Lee K, Kim JM, et al., 2021, Selenoprotein W Ensures Physiological Bone Remodeling by Preventing Hyperactivity of Osteoclasts. Nature Communications, 12: 2258.
[59] Zhang JQ, Takahashi A, Gu JY, et al., 2021, In Vitro and In Vivo Detection of Tunneling Nanotubes in Normal and Pathological Osteoclastogenesis Involving Osteoclast Fusion. Laboratory Investigation: A Journal of Technical Methods and Pathology, 101: 1571–1584.
[60] Ma Y, Shi X, Zhao H, et al., 2022, Potential Mechanisms of Osteoprotegerin-Induced Damage to Osteoclast Adhesion Structures via P2X7R-Mediated MAPK Signaling. International Journal of Molecular Medicine, 49: 1–12.
[61] Kukita T, Hiura H, Gu JY, et al., 2021, Modulation of Osteoclastogenesis through Adrenomedullin Receptors on Osteoclast Precursors: Initiation of Differentiation by Asymmetric Cell Division. Laboratory Investigation, 101: 1449–1457.
[62] Hasegawa T, Ishii M, 2022, Pathological Osteoclasts and Precursor Macrophages in Inflammatory Arthritis. Frontiers in Immunology, 13: 867368.
[63] Zhang W, Noller K, Crane J, et al., 2023, RANK(+)TLR2(+) Myeloid Subpopulation Converts Autoimmune to Joint Destruction in Rheumatoid Arthritis. eLife, 12: e85553.
[64] Das A, Saeki K, Dell'Orso S, et al., 2025, Integrative Single-Cell RNA-Seq and ATAC-Seq Identifies Transcriptional and Epigenetic Blueprint Guiding Osteoclastogenic Trajectory. Journal of Bone and Mineral Research, 40: 1127–1143.
[65] Zhang Y, Sun H, Huang F, et al., 2024, The Chromatin Remodeling Factor Arid1a Cooperates with Jun/Fos to Promote Osteoclastogenesis by Epigenetically Upregulating Siglec15 Expression. Journal of Bone and Mineral Research, 39: 775–790.
[66] Liao R, Dewey MJ, Rong J, et al., 2024, Matrix-Bound Nanovesicles Alleviate Particulate-Induced Periprosthetic Osteolysis. Science Advances, 10: eadn1852.
[67] Ma J, Zhu L, Zhou Z, et al., 2021, The Calcium Channel TRPV6 Is a Novel Regulator of RANKL-Induced Osteoclastic Differentiation and Bone Absorption Activity through the IGF-PI3K-AKT Pathway. Cell Proliferation, 54: e12955.
[68] Wu J, Zhang B, Du W, et al., 2025, OC-STAMP Is a Potential Biomarker and Therapeutic Target for Silicosis: An Exploratory Investigation. Journal of Translational Medicine, 23: 214.
[69] Tsukasaki M, Huynh NC, Okamoto K, et al., 2020, Stepwise Cell Fate Decision Pathways during Osteoclastogenesis at Single-Cell Resolution. Nature Metabolism, 2: 1382–1390.
[70] Okusha Y, Tran MT, Itagaki M, et al., 2020, Rab11A Functions as a Negative Regulator of Osteoclastogenesis through Dictating Lysosome-Induced Proteolysis of c-Fms and RANK Surface Receptors. Cells, 9: –.
[71] Jagannatha P, Tankka AT, Lorenz DA, et al., 2024, Long-Read Ribo-STAMP Simultaneously Measures Transcription and Translation with Isoform Resolution. Genome Research, 34: 2012–2024.
[72] Zhu L, Tang Y, Li XY, et al., 2023, A Zeb1/MtCK1 Metabolic Axis Controls Osteoclast Activation and Skeletal Remodeling. The EMBO Journal, 42: e111148.
[73] Ha MT, Tran PT, Tran HNK, et al., 2021, Anti-Osteoclastogenic Effects of Indole Alkaloids Isolated from Barley (Hordeum Vulgare Var. Hexastichon) Grass. Journal of Agricultural and Food Chemistry, 69: 12994–13005.