Regulatory Mechanism of Osteoclastogenesis by RANKL and Wnt Signals

Abstract

Osteoclasts develop from monocyte-macrophage lineage cells under the regulation of osteoblasts. Osteoblasts express two cytokines essential for osteoclastogenesis, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-KappaB ligand (RANKL). Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL, which inhibits the interaction between RANKL and RANK, a receptor of RANKL. Bone resorption-stimulating factors act on osteoblasts to regulate RANKL and OPG expression. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) is a master transcription factor for osteoclast differentiation. The immunoreceptor tyrosine-based activation motif (ITAM)-mediated signal was discovered as a co-stimulatory signal in RANKL-induced osteoclastogenesis. Wnt proteins activate two pathways: beta-catenin-dependent canonical and beta-catenin-independent noncanonical pathways. Wnt proteins promote differentiation of osteoblasts through the canonical pathway. The canonical pathway in osteoblasts also suppresses osteoclastogenesis through up-regulation of OPG expression and down-regulation of RANKL expression. In contrast, activation of the noncanonical pathway in osteoclast precursors enhances RANKL-induced osteoclastic differentiation. Thus, Wnt signals in osteoblasts and osteoclast precursors play important roles in osteoclastogenesis. This review summarizes the regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals.

The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures

“…A recent study demonstrated that Wnt5a, via noncanonical Wnt signaling, enhanced RANKL-induced osteoclast formation in mouse bone marrow macrophage cultures (50,51). Thus, it is possible that overproduction of Wnt5a in osteoblasts after SCI plays dual roles in unloading related-bone loss by compromising the beneficial role of increased Wnt3a on bone formation after SCI and promoting osteoclastogenesis and bone resorption by increasing RANKL production.…”

Osteogenic Differentiation of Stem Cells Alters Vitamin D Receptor Expression

“…VDR and PDIA3 are receptors for 1a,25(OH) 2 D 3 ; osteoprotegerin (OPG) is secreted by differentiated osteoblasts [41]; osteopontin is a 1a,25(OH) 2 D 3 -sensitive extracellular matrix protein that possesses a VDRE [42] and is regulated via PDIA3 [39]; and a2b1 integrin expression is associated with osteoblast differentiation through collagen type 1 recognition [43,44].…”

hRpn13, a newly identified component of the 19S particle, regulates proliferation, differentiation, and function in the human osteoblast-like cell line MG63

“…Among these factors is the crosstalk between osteoprotegerin (OPG), the receptor activator of nuclear factor κ-B (RANK), and its ligand RANKL. OPG can combine with RANKL in competition with RANK, inhibiting the RANKL-RANK system and arresting osteoclasts differentiation [23,25]. Accordingly, the altered balance between OPG and RANKL activity has been shown to play pivotal roles in the development of osteoporosis in animals and man [2].…”