Adipocytes regulate osteogenesis in a novel lipoatrophic mouse model

Abstract

Introduction: Substantial clinical evidence demonstrating a complex relationship between adiposity and osteoporosis suggests that adipose tissue plays an important role in bone metabolism. However, the exact function of adipocytes and mechanisms underlying its impact on bone health are yet incompletely understood due to marked discrepancies in human and animal studies. In this study, the effect of adipocytes on osteogenesis was explored using a novel lipodystrophic mouse model. Methods: We generated adipose tissue-specific murine double minute 2 knockout (KO) mice with Cre/loxP system. Knockout mice displayed gradually loss of peripheral adipose tissue and bone marrow adipocytes until nearly 80% to 100% of total fat reduction at 12-week-old mice. Results: Micro-computed tomography revealed that bone mineralisation density of femur from 12-week-old KO mice was significantly higher than the wild-type (WT) mice. Interestingly, the absence of adipocytes in KO mice exhibited markedly lower serum levels of C-terminal telopeptides of type I collagen (bone resorption marker) than WT mice, whereas the N-terminal propeptides of type I collagen (bone formation marker) remained unaffected. No differences were observed in the ex vivo differentiation of osteoblasts and osteoclasts between WT and KO mice. In addition, adipocyte-conditioned media treatment of isolated haematopoietic stem cells from bone marrow enhanced the differentiation of osteoclasts. Conclusion: These results indicate that secreted factors from adipocytes may promote osteoclastogenesis of haematopoietic stem cells. In summary, mature adipocytes suppress osteogenesis by enhancing the formation of osteoclasts, which eventually lead to low bone mass. Further studies are required to find out the novel factor and its detailed underlying mechanism in promoting osteoclastogenesis.