An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion
Open accessAbstract
Osteoporosis (OP) is a common age-related disease characterized by a deterioration of bone mass and structure that predisposes patients to fragility fractures. Pharmaceutical therapies that promote anabolic bone formation in OP patients and OP-induced fracture are needed. We investigated whether a neutralizing antibody against Siglec-15 can simultaneously inhibit bone resorption and stimulate bone formation. We found that the multinucleation of osteoclasts was inhibited in SIGLEC-15 conditional knockout mice and mice undergoing Siglec-15 neutralizing antibody treatment. The secretion of platelet-derived growth factor-BB (PDGF-BB), the number of tartrate-resistant acid phosphatase-positive (TRAP+) mononuclear cells, and bone formation were significantly increased in the SIGLEC-15 conditional knockout mice and antibody-treated mice. The anabolic effect of the Siglec-15 neutralizing antibody on bone formation was blunted in mice with Pdgfb deleted in TRAP+ cells. These findings showed that the anabolic effect of the Siglec-15 neutralizing antibody was mediated by elevating PDGF-BB production of TRAP+ mononuclear cells. To test the therapeutic potential of the Siglec-15 neutralizing antibody, we injected the antibody in an ovariectomy-induced osteoporotic mouse model, which mimics postmenopausal osteoporosis in women, and in two fracture healing models because fracture is the most serious health consequence of osteoporosis. The Siglec-15 neutralizing antibody effectively reduced bone resorption and stimulated bone formation in estrogen deficiency-induced osteoporosis. Of note, the Siglec-15 neutralizing antibody promoted intramembranous and endochondral ossification at the damaged area of cortical bone in fracture healing mouse models. Thus, the Siglec-15 neutralizing antibody shows significant translational potential as a novel therapy for OP and bone fracture.
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Antibodies targeting these molecules have also been developed.
“Antibodies targeting these molecules have also been developed52.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [52]
Molecules affecting osteoclast fusion and angiogenesis, such as SIGLEC15, L-plastin, and TLR2, have been successively discovered.
“Since then, molecules affecting osteoclast fusion and angiogenesis, such as SIGLEC15, L-plastin, and TLR2, have been successively discovered52–54.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [52]
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References 37 · Cited by 47
- Authors
- Zhen, G., Dan, Y., Wang, R., Dou, C., Guo, Q., Zarr, M., Liu, L. N., Chen, L., Deng, R., Li, Y., Shao, Z., & Cao, X.
- Affiliations
- Johns Hopkins University (US)
- Yale University (US)
- Wuhan Union Hospital (CN)
- Corresponding author
- Cao, Xu
- Venue
- Bone Research
- Published
- 2021-11-01
- Volume
- 9
- Issue
- 1
- Pages
- 47-47
- ISSN
- 2095-4700 (ISSN-L)
- 2095-6231
- PMC
- PMC8558327
- OpenAlex
- W3209354358
- Cited by
- 47
- References
- 37
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 13 · 2022: 5
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Bone Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- This research was partially supported by a grant from NextCure Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Medicinal Plant Pharmacodynamics Research
- Keywords
- Siglec-15, neutralizing antibodies, osteoporosis, fracture healing, bone formation, bone resorption, PDGF-BB, ovariectomy-induced osteoporosis, postmenopausal osteoporosis, endochondral ossification, intramembranous ossification
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