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 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.

Pulsed electromagnetic fields as a promising therapy for glucocorticoid-induced osteoporosis

“…Fusion of mononuclear precursor cells forms giant multinucleated cells in various ways (Xu and Teitelbaum, 2013). Mature osteoclasts are multinuclear cells produced by the fusion of tartrate-resistant acid phosphatase-positive (TRAP + ) mononuclear cells, termed preosteoclasts (POCs), and are the main source of platelet-derived growth factor-BB (PDGF-BB) (Boyle et al, 2003;Xu and Teitelbaum, 2013;Kusumbe et al, 2014;Xie et al, 2014;Zhen et al, 2021). Type H vessels are located abundantly in the metaphysis adjacent to the growth plate, are linked with bone formation, and are double-positive for CD31 and Emcn (Peng et al, 2020a;Zhen et al, 2021).…”

Endothelial PDGF-BB/PDGFR-β signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation

“… 24 – 26 Knockout of PDGF-BB in tartrate-resistant acid phosphatase-positive (TRAP + ) mononuclear cells impaired angiogenesis-coupled osteogenesis, 24 whereas bone formation and even fracture healing were enhanced if PDGF-BB expression in TRAP + mononuclear cells was elevated. 27 Moreover, abnormal overexpression of PDGF-BB in preosteoclasts resulted in vascular and skeletal disorders such as arterial stiffening and OA. 28 , 29 Su W et al recently revealed that excessive secretion of PDGF-BB from preosteoclasts promoted aberrant angiogenesis-dependent bone formation in subchondral bone, leading to OA pathogenesis.…”

Phytol Suppresses Osteoclast Differentiation and Oxidative Stress through Nrf2/HO-1 Regulation in RANKL-Induced RAW264.7 Cells

“…Phytol-mediated RANKL-induced osteoclast differentiation inhibition was demonstrated in this study. Mononuclear TRAP-positive cells fuse to form mature osteoclasts, which are the primary cells for bone resorption [ 30 ]. In addition, the formation of multinucleated cells and F-actin denote osteoclast-specific structures and bone resorption, respectively [ 31 , 32 ].…”