Abstract
Osteoporosis and bone disorders related to the metabolic syndrome are often associated with adipokines secreted by adipocytes in bone. Adiponectin, a type of adipokine, is a regulator of immune responses and metabolic processes, but its role in bone biology remains uncertain. We investigated the role of adiponectin in bone metabolism using adiponectin-deficient mice in vivo and in vitro. Adiponectin-deficient mice exhibited reduced bone mass and increased adiposity. Adiponectin-deficient calvarial cells were prone to differentiate into adipocytes rather than osteoblasts. Although bone marrow macrophages (BMMs) from adiponectin-deficient mice had low osteoclastogenic potential as osteoclast precursors with increasing interferon regulatory factor 5 expression, under co-culture conditions of calvarial cells and BMMs, the enhanced receptor activator of nuclear factor κB ligand/osteoprotegerin (RANKL/OPG) ratio of adiponectin-deficient mesenchymal progenitor cells facilitated osteoclast differentiation. In addition, increased RANKL/OPG ratio was observed in the bone marrow extracellular fluid of adiponectin-deficient mice compared to that of wild-type mice. Notably, recombinant adiponectin treatment enhanced RANKL-induced osteoclast differentiation from BMMs but up-regulated OPG production in recombinant adiponectin-exposed calvarial cells, which inhibited osteoclast differentiation. Taken together, these results suggest that adiponectin plays an inhibitory role in bone metabolism through cross talk between precursor cells of both osteoclasts and osteoblasts by regulating RANKL/OPG ratio in the bone marrow microenvironment.
Highlights
The bone marrow microenvironment, which determines the fates of bone-resorbing osteoclasts and bone forming-osteoblasts, is an important region for bone metabolism [1]
Adiponectin-deficient macrophages are seemingly inefficient for osteoclast differentiation on a per cell basis, since equal number of macrophages from wild-type and adiponectin-deficient mice was used for osteoclast differentiation assay
The expression of IRF5, a master factor for polarizing M1 macrophages, was greater in CD11b-positive osteoclast precursors from Peripheral blood mononuclear cells (PBMCs) and peritoneal cells from adiponectin-deficient mice than in those from wild-type mice, whereas it was similar in CD11bpositive bone marrow cells
Summary
The bone marrow microenvironment, which determines the fates of bone-resorbing osteoclasts and bone forming-osteoblasts, is an important region for bone metabolism [1]. Osteoblasts, which are derived from mesenchymal stem cells, contribute to bone formation along with secretion of bone matrix by activating Runx, osterix, or β-catenin as well as osteoclast differentiation by producing RANKL and OPG [2, 4]. Under pathophysiological conditions such as osteoporosis and aging, mesenchymal stem cells are prone to differentiate into adipocytes rather than osteoblasts, resulting in increased adiposity and decreased bone formation [5]. IL-6 and TNF-α suppress osteoblast differentiation and enhance osteoclast differentiation, but mice lacking these cytokines exhibit normal bone phenotypes [7]. Leptin-deficient mice exhibit either high or low bone mass, depending on skeletal region [8]
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