An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion

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

doi:10.1038/s41413-021-00161-1

An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP⁺ mononuclear cells and PDGF-BB secretion

Bone Res. 2021 Nov 1;9(1):47. doi: 10.1038/s41413-021-00161-1.

Authors

Gehua Zhen^#¹, Yang Dan^#^{1

2}, Ruomei Wang¹, Ce Dou¹, Qiaoyue Guo¹, Melissa Zarr³, Linda N Liu³, Lieping Chen⁴, Ruoxian Deng^{1

5}, Yusheng Li¹, Zengwu Shao², Xu Cao^{6

7}

Affiliations

¹ Department of Orthopedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ NextCure, Inc., Beltsville, MD, USA.
⁴ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Orthopedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. xcao11@jhmi.edu.
⁷ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. xcao11@jhmi.edu.

^# Contributed equally.

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.

Grants and funding

P01 AG066603/AG/NIA NIH HHS/United States