Complement C3 deficiency inhibits osteoclast differentiation and prevents ovariectomy-induced osteoporosis.

Abstract

The pathomechanistic role of the complement system is well recognized in various pathological conditions affecting bone tissues and the bone microenvironment, including rheumatoid arthritis, osteoarthritis, bone fractures, and periodontitis. The homeostasis of the bone is maintained by continuous remodeling, in which bone-resorbing or demineralizing osteoclast cells remove bone calcification, and osteoblast cells deposit new bone matrix. Major complement protein C3 is reported to control endochondral ossification, cartilage-to-bone transition, and longitudinal bone growth. The role of the complement protein C3 in differentiating multinucleated osteoclast cells (bone-resorbing cells) from osteoclast precursor cells (OCPs) and its contribution to long bone microarchitecture and strength are unclear. We demonstrated that C3 promotes the differentiation of osteoclasts and the formation of multinucleated osteoclasts from bone marrow-derived OCPs. C3-/- mice OCPs had reduced osteoclast-associated gene expression of TRAP (tartrate-resistant acid phosphatase), cathepsin K, calcitonin receptor, and RANK (receptor activator of nuclear factor κB) molecules compared with osteoclasts derived from wild-type (WT) OCPs. C3-/- mice had significantly increased bone mineral density and other bone parameters of the femur compared with WT mice. Furthermore, compared with WT mice, C3-/- mice were protected from ovariectomy-induced osteoporosis, characterized by significantly increased Foxp3+CD4+ T cells in the spleen and interleukin-10-producing B cells in both the spleen and the bone marrow. Intriguingly, C3 knockout mice exhibit reduced differentiation of functional osteoclast cells, which promotes a strong bone microarchitecture, suggesting that complement pathways may be explored as a therapeutic target in bone inflammatory diseases.