Abstract
The coordinated development and function of bone-forming (osteoblasts) and bone-resorbing (osteoclasts) cells is critical for the maintenance of skeletal integrity and calcium homeostasis. An enhanced adipogenic versus osteogenic potential of bone marrow mesenchymal stem cells (MSCs) has been linked to bone loss associated with diseases such as diabetes mellitus, as well as aging and postmenopause. In addition to an inherent decrease in bone formation due to reduced osteoblast numbers, recent experimental evidence indicates that an increase in bone marrow adipocytes contributes to a disproportionate increase in osteoclast formation. Therefore, a potential strategy for therapeutic intervention in chronic bone loss disorders such as osteoporosis is to interfere with the pro-osteoclastogenic influence of marrow adipocytes. However, application of this approach is limited by the extremely complex regulatory processes in the osteoclastogenic program. For example, key regulators of osteoclastogenesis such as the receptor activator of nuclear factor-kappaB ligand (RANKL) and the soluble decoy receptor osteoprotegerin (OPG) are not only secreted by both osteoblasts and adipocytes, but are also regulated through several cytokines produced by these cell types. In this context, biologically active signaling molecules secreted from bone marrow adipocytes, such as chemerin, adiponectin, leptin, visfatin and resistin, can have a profound influence on the osteoclast differentiation program of hematopoietic stem cells (HSCs), and thus, hold therapeutic potential under disease conditions. In addition to these paracrine signals, adipogenic transcription factors including CCAAT/enhancer binding protein alpha (C/EBPα), C/EBP beta (C/EBPβ) and peroxisome proliferator-associated receptor gamma (PPARγ) are also expressed by osteoclastogenic cells. However, in contrast to MSCs, activation of these adipogenic transcription factors in HSCs promotes the differentiation of osteoclast precursors into mature osteoclasts. Herein, we discuss the molecular mechanisms that link adipogenic signaling molecules and transcription factors to the osteoclast differentiation program and highlight therapeutic strategies targeting these mechanisms for promoting bone homeostasis.
Highlights
Bone is a dynamic connective tissue that continuously undergoes homeostatic remodeling throughout life via a tightly regulated balance between the resorption of old bone and the formation of new bone tissue [1,2,3,4,5,6,7]
Two distinct self-renewing populations of multipotent stem cells reside within bone marrow—mesenchymal stem cells (MSCs) that give rise to the mesenchymal lineages, including osteoblasts and hematopoietic stem cells (HSCs) that give rise to all blood cell types including the monocyte lineage, from which osteoclasts are derived [3,6,8]
Among the isoforms of receptor activator of nuclear factor-kappa B ligand (RANKL) produced in bone marrow, the membrane-bound form, which requires cell-to-cell contact between osteoblast precursors and HSCs for activity, is more effective than the secreted soluble forms at promoting osteoclastogenesis [11,12]
Summary
Bone is a dynamic connective tissue that continuously undergoes homeostatic remodeling throughout life via a tightly regulated balance between the resorption of old bone and the formation of new bone tissue [1,2,3,4,5,6,7]. Consistent with the competitive nature of lineage allocation, adipogenic transcription factors including peroxisome proliferator-associated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα) have been shown to suppress the MSC osteoblastogenic program [3,19,20,21,22]. The activities of these adipogenic transcription factors, as well as osteoblastogenic signaling pathways such as Wnt/β-catenin are influenced by extracellular factors present within the local bone microenvironment. We discuss recent progress in the understanding of the influence of adipogenic events on the osteoclast differentiation program and highlight the future therapeutic potential for targeting these pathways to promote bone regeneration in disorders of bone loss
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