Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis

Abstract

The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.

Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin

“…5 A). In contrast, Wnt5a, a ligand known to activate noncanonical Wnt signaling pathways, did not inhibit, but activated osteoclast differentiation, in line with data published by others (Maeda et al, 2012). Because the induction of Fzd8 expression during osteoclastogenesis occurs before the (CRD; Fig.…”

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

“…Wnt5a may therefore represent a possible target to block ossification in AS. In addition to preventing excessive bone formation, inhibition of Wnt5a may also reduce the neighboring bone resorption that characterize patients with AS, since osteoblast-derived Wnt5a stimulates osteoclastogenesis [42]. Finally, Wnt5a blockade may also impact the secretion of inflammatory mediators such as IL-6, IL-1b and IL-8 [38].…”

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.…”