At the Crossroads of the Adipocyte and Osteoclast Differentiation Programs: Future Therapeutic Perspectives

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.

Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells

“…In addition to osteoblasts, MSCs are also able to differentiate into adipocytes within bone marrow microenvironment. Increasing evidence suggests that the differentiation of MSCs into adipocytes or osteoblasts is competitively balanced (Li et al, 2016), and this delicate balance is important for the maintenance of bone homeostasis (Hu et al, 2018b;Muruganandan et al, 2020). Dysregulation of osteo-adipogenic differentiation balance of MSCs contributes to development of bone diseases, such as osteoporosis, which manifests typically as a lineage shift toward adipocytes instead of osteoblasts in MSCs (Qi et al, 2017).…”

Molecular Mechanisms and Emerging Therapeutics for Osteoporosis

“…Bone marrow adipogenesis plays a critical role in bone loss associated with aging as well as diseases such as diabetes mellitus. The differentiation of adipocytes derived from MSC in bone marrow competes with osteoblastogenesis by its nature of lineage allocation while the mature adipocytes express RANKL and promote osteoclastogenesis [ 83 , 84 ]. Notably, among the adipogenic transcription factors, including CCAAT/enhancer binding protein alpha (C/EBPα), C/EBPβ, and peroxisome proliferator-associated receptor gamma (PPARγ), PPARγ is considered as a master factor for osteoclast differentiation from HSCs [ 85 ].…”

“…Furthermore, chemerin/CMKLR1 signaling induces expression of NFATc1 in HSCs, a key transcription factor for osteoclast differentiation, demonstrating that chemerin may potentiate bone loss in disease states [ 88 ]. Other adipokines such as visfatin and resistin represented similar activity, although the role of visfatin in bone remodeling is controversial [ 83 ]. Collectively, bone formation is regulated by the cell-to-cell contact involving RANK-RANKL in normal condition, however, adipocytes as well as adipokines can play critical roles in bone-loss-associated diseases.…”

<p>Role of αVβ3 in Prostate Cancer: Metastasis Initiator and Important Therapeutic Target</p>

“…RANKL induces osteoblasts to differentiate into osteoclasts and initiates osteolysis. 43 Hydroxyapatite (HA) is exposed on the surface of the dissolved bone, and this structure promotes tumor cell immobilization on the bone surface via αVβ3. 44 Bongjun Kim et al confirmed that acetylated RUNX2 induces RANKL expression, and protein acetylation was attributed to the fact that integrin αVβ3 mediates CCN2-stimulated acetylation and stabilization of RUNX2 in highly bonemetastatic cancer cells ( Figure 1).…”