An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion
Abstract 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 wh...
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Nature Publishing Group
2021
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oai:doaj.org-article:a8554920a26d4080a2d68a5e92d3aeba2021-11-07T12:09:11ZAn antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion10.1038/s41413-021-00161-12095-6231https://doaj.org/article/a8554920a26d4080a2d68a5e92d3aeba2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41413-021-00161-1https://doaj.org/toc/2095-6231Abstract 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.Gehua ZhenYang DanRuomei WangCe DouQiaoyue GuoMelissa ZarrLinda N. LiuLieping ChenRuoxian DengYusheng LiZengwu ShaoXu CaoNature Publishing GrouparticleBiology (General)QH301-705.5PhysiologyQP1-981ENBone Research, Vol 9, Iss 1, Pp 1-11 (2021) |
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Biology (General) QH301-705.5 Physiology QP1-981 |
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Biology (General) QH301-705.5 Physiology QP1-981 Gehua Zhen Yang Dan Ruomei Wang Ce Dou Qiaoyue Guo Melissa Zarr Linda N. Liu Lieping Chen Ruoxian Deng Yusheng Li Zengwu Shao Xu Cao An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion |
| description |
Abstract 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. |
| format |
article |
| author |
Gehua Zhen Yang Dan Ruomei Wang Ce Dou Qiaoyue Guo Melissa Zarr Linda N. Liu Lieping Chen Ruoxian Deng Yusheng Li Zengwu Shao Xu Cao |
| author_facet |
Gehua Zhen Yang Dan Ruomei Wang Ce Dou Qiaoyue Guo Melissa Zarr Linda N. Liu Lieping Chen Ruoxian Deng Yusheng Li Zengwu Shao Xu Cao |
| author_sort |
Gehua Zhen |
| title |
An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion |
| title_short |
An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion |
| title_full |
An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion |
| title_fullStr |
An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion |
| title_full_unstemmed |
An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion |
| title_sort |
antibody against siglec-15 promotes bone formation and fracture healing by increasing trap+ mononuclear cells and pdgf-bb secretion |
| publisher |
Nature Publishing Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/a8554920a26d4080a2d68a5e92d3aeba |
| work_keys_str_mv |
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1718443507559956480 |