Treatment with Soluble Activin Type IIB Receptor Ameliorates Ovariectomy-Induced Bone Loss and Fat Gain in Mice

Abstract

Introduction: In postmenopausal osteoporosis, hormonal changes lead to increased bone turnover and metabolic alterations including increased fat mass and insulin resistance. Activin type IIB receptors bind several growth factors of the TGF-β superfamily and have been demonstrated to increase muscle and bone mass. We hypothesized that ActRIIB-Fc treatment could improve bone and muscle mass, inhibit fat accumulation, and restore metabolic alterations in an ovariectomy (OVX) model of postmenopausal osteoporosis. Materials and Methods: Female C57Bl/6 N mice were subjected to SHAM or OVX procedures and received intraperitoneal injections of either PBS or ActRIIB-Fc (5 mg/kg) once weekly for 7 weeks. Glucose and insulin tolerance tests (GTT and ITT, respectively) were performed at 7 and 8 weeks, respectively. Bone samples were analyzed with micro-computed tomography imaging, histomorphometry, and quantitative RT-PCR. Results: Bone mass decreased in OVX PBS mice compared to the SHAM PBS group but ActRIIB-Fc was able to prevent these changes as shown by µCT and histological analyses. This was due to decreased osteoclast numbers and function demonstrated by histomorphometric and qRT-PCR analyses. OVX induced adipocyte hypertrophy that was rescued by ActRIIB-Fc, which also decreased systemic adipose tissue accumulation. OVX itself did not affect glucose levels in GTT but ActRIIB-Fc treatment resulted in impaired glucose clearance in both SHAM and OVX groups. OVX induced mild insulin resistance in ITT but ActRIIB-Fc treatment did not affect this. Conclusion: Our results reinforce the potency of ActRIIB-Fc as a bone-enhancing agent but also bring new insight into the metabolic effects of ActRIIB-Fc in normal and OVX mice.