In Vitro and in Vivo Effects of Adiponectin on Bone

Abstract

Fat mass impacts on both bone turnover and bone density and is a critical risk factor for osteoporotic fractures. Adipocyte-derived hormones may contribute to this relationship, and adiponectin is a principal circulating adipokine. However, its effects on bone remain unclear. We have, therefore, investigated the direct effects of adiponectin on primary cultures of osteoblastic and osteoclastic cells in vitro and determined its integrated effects in vivo by characterizing the bone phenotype of adiponectin-deficient mice. Adiponectin was dose-dependently mitogenic to primary rat and human osteoblasts ( approximately 50% increase at 10 microg/ml) and markedly inhibited osteoclastogenesis at concentrations of 1 microg/ml or greater. It had no effect on osteoclastogenesis in RAW-264.7 cells or on bone resorption in isolated mature osteoclasts. In adiponectin knockout (AdKO) male C57BL/6J mice, trabecular bone volume and trabecular number (assessed by microcomputed tomography) were increased at 14 wk of age by 30% (P = 0.02) and 38% (P = 0.0009), respectively. Similar, nonsignificant trends were observed at 8 and 22 wk of age. Biomechanical testing showed lower bone fragility and reduced cortical hardness at 14 wk. We conclude that adiponectin stimulates osteoblast growth but inhibits osteoclastogenesis, probably via an effect on stromal cells. However, the AdKO mouse has increased bone mass, suggesting that adiponectin also has indirect effects on bone, possibly through modulating growth factor action or insulin sensitivity. Because adiponectin does influence bone mass in vivo, it is likely to be a contributor to the fat-bone relationship.

AMP-activated protein kinase pathway and bone metabolism

“…The hormonal regulation of AMPK activation in bone has not been extensively studied. Adiponectin, which increases osteoblast proliferation and differentiation (Oshima et al 2005) but has controversial effect on bone mass in vivo (Williams et al 2009), can stimulate AMPK phosphorylation in MC3T3-E1 osteoblastic cells (Kanazawa et al 2007). We showed that AMPK phosphorylation and activity in ROS17/2.8 cells was stimulated by ghrelin (Shah et al 2010), a hormone known to stimulate osteoblast differentiation and function (Maccarinelli et al 2005, van der Velde et al 2008.…”

“…The bone loss in age-related osteoporosis is associated with more adipogenesis and less bone formation (Pei & Tontonoz 2004). Second, there are direct actions on bone of hormones produced by adipocytes, such as adiponectin and leptin, as well as of hormones released by the pancreas, gut and pituitary (Cornish et al 1996, Maccarinelli et al 2005, Williams et al 2009). In addition, the recent discovery that leptin can inhibit bone formation through hypothalamic and sympathetic nervous system relays , Takeda et al 2002, Elefteriou et al 2005 has demonstrated that bone can not only be directly affected by hormones which have receptors on bone cells, but can also be influenced by the same hormones acting on receptors in the central nervous system (CNS).…”

The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis

“…In vitro studies also found that this adipokine promotes osteoblastogenesis but negatively regulates adipogenesis [116][117][118]. However, in vivo studies with adiponectin-deficient mice showed agedependent increase in trabecula volume and number suggesting that adiponectin has both direct and indirect effects on bone in vivo, and is also a likely contributor to bone mass [118]. The role of other adipokines in MSC differentiation is less clear, however, recent findings suggest that most of these adipokines may play a role in regulating bone metabolism and remodeling [98].…”

“…Adiponectin is another adipose secreted adipokine with critical roles in glucose metabolism and energy homeostasis [115]. In vitro studies also found that this adipokine promotes osteoblastogenesis but negatively regulates adipogenesis [116][117][118]. However, in vivo studies with adiponectin-deficient mice showed agedependent increase in trabecula volume and number suggesting that adiponectin has both direct and indirect effects on bone in vivo, and is also a likely contributor to bone mass [118].…”

Osteoblast-specific expression of Fra-2/AP-1 controls Adiponectin/Osteocalcin expression and affects metabolism

“…Studies in vitro and in vivo have yielded contradictory results regarding the effects of Adipoq on bone cell function. Adipoq has been shown to either stimulate or suppress osteogenesis in vitro (Lee et al, 2009;Shinoda et al, 2006;Williams et al, 2009) and the results from in vivo studies using Adipoq knockout or overexpressing mice are also conflicting (Ealey et al, 2008;Oshima et al, 2005;Shinoda et al, 2006;Williams et al, 2009). This indicates that Adipoq could additionally contribute to the bone phenotype by suppressing bone forming activity in osteoblasts in an autocrine fashion.…”