Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors

Abstract

Bone remodeling in physiological and pathological conditions represents a balance between bone resorption mediated by osteoclasts and bone formation by osteoblasts. Bone resorption is tightly and dynamically regulated by multiple mediators, including cytokines that act directly on osteoclasts and their precursors, or indirectly by modulating osteoblast lineage cells that in turn regulate osteoclast differentiation. The critical role of cytokines in inducing and promoting osteoclast differentiation, function and survival is covered by the accompanying review by Zwerina and colleagues. Recently, it has become clear that negative regulation of osteoclastogenesis and bone resorption by inflammatory factors and cytokines, downstream signaling pathways, and a newly described network of transcriptional repressors plays a key role in bone homeostasis by fine tuning bone remodeling and restraining excessive bone resorption in inflammatory settings. In this review we discuss negative regulators of osteoclastogenesis and mechanisms by which these factors suppress bone resorption.

Figure 1

Regulation of osteoclast differentiation. Osteoclasts are derived from myeloid precursors. Macrophage colony-stimulating factor (M-CSF) induces myeloid precursors to differentiate to osteoclast precursors that express RANK (Receptor activator of NF-κB) and TREM2 (Triggering receptor expressed by myeloid cells-2) receptors. Upon RANK ligand (RANKL) stimulation and ITAM (Immunoreceptor tyrosine-based activation motif) activation, osteoclast precursors undergo further differentiation to mononuclear osteoclasts with NFATc1 (Nuclear factor of activated T cells, cytoplasmic 1) induction and express osteoclast-related genes such as those encoding TNF-receptor associated protein (TRAP), cathepsin K (CtsK) and αvβ3. Mononuclear osteoclasts then fuse to multinuclear osteoclasts and function as polarized bone resorbing cells. This process of osteoclast differentiation is regulated by various transcription factors and exogenous factors at different stages. Inflammatory factors that promote osteoclastogenesis are shown in red. Inhibitors of osteoclastogenesis are shown in blue. Calc, calcitonin; Calc R, calcitonin receptor; CSF-1R, colony stimulating factor 1 receptor; DC-STAMP, dendritic cell-specific transmembrane protein; ECM, extracellular matrix; GM-CSF, granulocyte-macrophage colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; MITF, microphthalmia-associated transcription factor; OPG, osteoprotegerin; TLR, Toll-like receptor.

Figure 2

Transcriptional regulatory network for osteoclastogenesis. RANK (Receptor activator of NF-κB) signaling together with calcium signaling drives expression of NFATc1 (Nuclear factor of activated T cells, cytoplasmic 1) and its targets, resulting in osteoclastogenesis. This process also requires releasing the 'brakes' on NFATc1 expression and osteoclastogenesis that are imposed by transcriptional repressors, including inhibitors of differentiation/DNA binding (Ids), MafB (v-maf musculoaponeurotic fibrosarcoma oncogene family protein B), interferon regulatory factor (IRF)-8 and B cell lymphoma 6 (Bcl6). There is crosstalk between the activating and suppressive pathways, as Blimp1 (B lymphocyte-induced maturation protein-1) that is induced by NFATc1 suppresses expression of MafB, IRF-8 and Bcl6. ITAM, immunoreceptor tyrosine-based activation motif; MAPK, mitogen-activated protein kinase.