Lipid metabolism disorders and bone dysfunction--interrelated and mutually regulated (review)

Abstract

The association between lipid and bone metabolism has become an increasing focus of interest in recent years, and accumulating evidence has shown that atherosclerosis (AS) and osteoporosis (OP), a disorder of bone metabolism, frequently co-exist. Fat and bone are known to share a common progenitor cell: Multipotent mesenchymal stem cells (MSC) in the bone marrow (BM), which are able to differentiate into various cell phenotypes, including osteoblasts, adipocytes and chondrocytes. Laboratory-based and clinical trials have shown that increasing adipocytes are accompanied by a decrease in bone mineral density (BMD) and bone mass. Statins, lipid-lowering drugs used to treat hyperlipidemia, also provide benefit in the treatment of OP. There is thus evidence that the metabolism of lipids is correlated with that of bone, and that the two are mutually regulated. The present review primarily focuses on the potential association between lipid metabolism disturbance and OP, based on biological metabolism, pathophysiological processes, results from clinical and experimental animal studies, processes involved in the differentiation of adipocytes and osteoblasts, as well as pharmacological treatments of these diseases.

Figure 1

Signaling pathway regulation of the differentiations of adipocytes and osteoblasts. Adipocytes and osteoblasts are derived from a common MSC pool. The balance of adipocyte and osteoblast differentiation requires communication between extracellular stimuli, as well as a coordinated network of receptors and transcription factors in the nucleus, including the RANKL/RANK/OPG and Wnt/β-catenin signaling pathway, along with PPARγ. Disordered lipid metabolism disorder may result in an increase in oxidized lipids. Oxidized lipids promote the differentiation of adipocytes and inhibit that of osteoblasts, by activating PPARγ. The sFRP-1 binds to the Wnt receptor and blocks the Wnt signaling pathway, thereby inhibiting osteoblast differentiation and promoting adipocyte differentiation. The low-activity Wnt signaling pathway in BMSCs enhances adipocyte differentiation by upregulating C/EBPα and PPARγ, whereas it suppresses osteoblast differentiation by downregulating Runx2 expression. Furthermore, low activity of the Wnt signaling pathway in osteoblasts down-regulates the expression of OPG, which leads to the enhancement of bone resorption by enforcing RANKL-induced osteoclastic differentiation based on the RANKL/RANK/OPG pathway. These changes ultimately increase bone fat deposition and promote the development of osteoporosis. MSC, mesenchymal stem cell; RANKL, receptor activator for nuclear factor κB ligand; OPG, osteoprotegerin, BMSC, bone marrow stromal cell; C/EBPα, CCAAT-enhancer binding proteins α; PPARγ, peroxisome proliferator-activated receptor γ; sFRP-1, secreted frizzled-related protein 1; Runx2, runt-related protein 2.

Figure 2

Leptin action on bone metabolism via the peripheral and central nervous systems. Leptin is an adipocytokine, which is primarily produced in white adipose tissue. Osteoblasts, osteoclasts and BMSCs express the leptin receptor. The direct peripheral action of leptin on bone occurs via binding to the Ob-R on BMSCs. Leptin suppresses adipogenic differentiation of BMSCs and promotes osteoblastic differentiation. In addition, leptin increases OPG production in association with reducing that of RANKL, thereby inhibiting osteoclastic differentiation. Leptin also exhibits a central indirect effect on bone by binding to its receptor in the hypothalamus and activating the SNS, enabling binding of noradrenalin to β2-AR on osteoblasts and thus inhibiting bone formation. It also increases RANKL expression and promotes the differentiation of osteoclasts. BMSC, bone marrow stromal cell; Ob-R, leptin receptor; OPG, osteoprotegerin; RANKL, receptor activator for nuclear factor κB ligand; SNS, sympathetic nervous system; β2-AR, β2-adrenergic receptor.