Mechanisms involved in normal and pathological osteoclastogenesis

Abstract

Osteoclasts are bone-resorbing cells that play an essential role in bone remodeling. Defects in osteoclasts result in unbalanced bone remodeling and are linked to many bone diseases including osteoporosis, rheumatoid arthritis, primary bone cancer, and skeletal metastases. Receptor activator of NF-kappaB ligand (RANKL) is a classical inducer of osteoclast formation. In the presence of macrophage-colony-stimulating factor, RANKL and co-stimulatory signals synergistically regulate osteoclastogenesis. However, recent discoveries of alternative pathways for RANKL-independent osteoclastogenesis have led to a reassessment of the traditional mechanisms that regulate osteoclast formation. In this review, we provide an overview of signaling pathways and other regulatory elements governing osteoclastogenesis. We also identify how osteoclastogenesis is altered in pathological conditions and discuss therapeutic targets in osteoclasts for the treatment of skeletal diseases.

Keywords: MYC; Osteoclastogenesis; Osteoclasts; RANK; RANKL.

Fig. 1

Signaling cascades on osteoclast differentiation. Osteoclastogenesis requires the activation of RANK signaling as well as ITAM-mediated co-stimulatory signals. RANK/RANKL interactions recruit TRAF6 and activate downstream signaling pathways; NF-κB pathways and MAPK pathways including ERK, JNK, and p38. NF-κB, AP-1 (c-FOS), and MYC are important downstream transcription factors for osteoclast formation and induce the expression of NFATc1, a master regulator of osteoclastogenesis. RANK signals also activate the ITAM receptor-mediated signaling pathway. Syk is recruited to phosphorylated ITAM adaptors (DAP12 or FcRγ), and then, Btk/Tec and BLNK/SLP-76 form a complex with PLCγ2. ITAM signals and RANK signals cooperatively induce Ca²⁺ oscillation, activate Ca^2+-dependent signaling pathways, and synergistically induce NFATc1. RANK receptor activator of nuclear factor-κB, RANKL receptor activator of nuclear factor-κB ligand, ITAM immunoreceptor tyrosine activation motif, DAP12 DNAX-activating protein 12, FcRγ Fc receptor common γ subunit, TRAF6 TNF receptor-associated factors 6, NF-κB nuclear factor-κB, aPCK atypical protein kinase C, IKK IκB kinase, TAK1 TGFβ-activated kinase 1, Gab2 growth factor receptor-bound protein 2 (Grb2)-associated binder-2, Syk spleen tyrosine kinase, PLCγ2 phospholipase Cγ2, TAB TAK1-binding protein, MAPKs mitogen-activated protein kinases, JNK c-Jun N-terminal kinase, ERK extracellular signal-regulated kinase, AP-1 activator protein-1, NFATc1 nuclear factor of activated T-cell cytoplasmic 1

Fig. 2

Negative-feedback regulation of osteoclastogenesis. Osteoclastogenesis is regulated in multiple levels. OPG is a soluble decoy receptor for RANKL and competes with RANK for binding RANKL. The RANK/RANKL/OPG system has an essential regulatory role in osteoclast biology. LRG4 is a new receptor for RANKL and maintains the balance of RANKL-mediated activation by competing with RANK and suppressing the activation of NFATc1 via Gαq–GSK3β signaling pathway. RANK/RANKL interactions induce IFNβ via c-FOS. Then, IFNβ binds to its receptors and transduces negative signals to suppress the expression of c-FOS. RANK signals also downregulate the negative regulators of osteoclastogenesis such as BCL6, MAFB, IRF8, and ID2 to counteract NFATc1-mediated induction of osteoclast-specific genes. RANK receptor activator of nuclear factor-κB, RANKL receptor activator of nuclear factor-κB ligand, OPG osteoprotegerin, NFATc1 nuclear factor of activated T-cell cytoplasmic 1, LRG4 leucine-rich repeat-containing G-protein-coupled receptor 4, GSK3 glycogen synthase kinase 3, IFNβ interferon-beta, BCL6 B-cell lymphoma 6, MafB V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B, IRF8 interferon regulatory factor-8, ID2 inhibitors of differentiation 2

Fig. 3

MYC–ERRα axis in osteoclast differentiation. RANKL stimulation activates downstream signaling molecules including c-Jun (AP1) and RelB (a signaling mediator in a non-canonical NF-κB pathway), and induces MYC expression. MYC stimulates the expression of ERRα and NFATc1 (shown in Fig. 1). ERRα induces genes for mitochondrial oxidative phosphorylation and the MYC–ERRα axis plays an important role in mitochondrial oxidative phosphorylation during osteoclast differentiation. The expression of PGC1β and other factors (X) is directly regulated by RelB and c-Jun and controls mitochondrial biogenesis. PGC1β also regulates the expression of c-FOS, a key factor of osteoclastogenesis. In addition, ERRα and PGC1β can form complexes in osteoclasts which have transcriptional activity. Cholesterol is a newly identified ligand for ERRα that enhances transcriptional activity of ERRα. In this vein, cholesterol-mediated enhancement of osteoclastogenesis is significantly reduced in ERRα-deficient mice. Although the role of PPARγ in in vivo bone resorption is controversial, rosiglitazone, a PPARγ agonist, increases bone loss and skeletal fragility by suppressing bone formation and enhancing bone resorption. PGC1β-deficient mice are resistant to rosiglitazone-induced bone loss. ERRα estrogen receptor-related alpha, PGC1β peroxisome proliferation-activated receptor-gamma coactivator 1b, PPARγ peroxisome proliferation-activated receptor-gamma