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.
Highlights
Siglec-15 is a member of the sialic acid-binding immunoglobulintype lectin (Siglecs) family, a group of cell-surface receptors that potentially regulate the adaptive immune response via cell–cell interactions with target cells through their sialic acid-binding N-terminal Ig-like V-type domain
Knockout of Siglec-15 in macrophage-lineage cells increased TRAP+ mononuclear cells and decreased osteoclastic bone resorption To investigate the role of Siglec-15+ osteoclast lineage cells during bone remodeling, we generated LysMCre:Siglec-15f/f (SKO) mice by crossing LysMCre mice with Siglec-15flox/flox mice
These findings suggest that the enhanced bone formation in the SKO mice was modulated indirectly by osteoclast lineage cells
Summary
Siglec-15 is a member of the sialic acid-binding immunoglobulintype lectin (Siglecs) family, a group of cell-surface receptors that potentially regulate the adaptive immune response via cell–cell interactions with target cells through their sialic acid-binding N-. Intermittent administration of PTH increases bone mass and strength.[12] because of the potential risk of inducing osteosarcoma and the high cost, PTH use has been limited to 2 years and is considered a “second-line” medication reserved for patients with severe osteoporosis at high risk of fracture.[13] The use of other antiresorptive osteoporosis medications is limited by their adverse effects. The results showed that the Siglec-15 neutralizing antibody increases bone formation in estrogen deficiency-induced osteoporosis and fracture healing mouse models
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