Wnt16 regulates osteoclast differentiation in conjunction with Wnt5a

Area of Science:

• Bone Biology
• Cell Signaling
• Endocrinology

Background:

• Canonical Wnt/β-catenin signaling inhibits osteoclastogenesis via osteoprotegerin (Opg).
• Non-canonical Wnt ligands like Wnt5a promote osteoclast formation by enhancing receptor activator of NF-κB (Rank) expression.
• Wnt16 and Wnt4 are known to inhibit osteoclastogenesis through non-canonical pathways, but their interactions are unclear.

Purpose of the Study:

• To elucidate the distinct roles of Wnt16, Wnt4, and Wnt3a in osteoclastogenesis.
• To investigate the interplay between Wnt16 and Wnt5a in regulating osteoclast formation and function.

Main Methods:

• Bone marrow-derived macrophage (BMM) cultures to assess osteoclastogenesis.
• Co-cultures from wild-type and Opg(-/-) mice to evaluate Wnt ligand effects.
• Assays for pit-forming activity to measure osteoclast function.
• Analysis of Rank expression in osteoclast precursors.

Main Results:

• Wnt16, but not Wnt4, inhibited receptor activator of NF-κB ligand (Rankl)-induced osteoclastogenesis in BMM cultures.
• Wnt3a and Wnt4 inhibited 1α,25-dihydroxy vitamin D3 (1,25D3)-induced osteoclastogenesis in wild-type, but not Opg(-/-), co-cultures.
• Wnt16 inhibited 1,25D3-induced osteoclastogenesis in both wild-type and Opg(-/-) co-cultures.
• Wnt16, Wnt4, and Wnt3a did not inhibit osteoclast pit-forming activity.
• Wnt5a abrogated Wnt16's inhibitory effect on Rankl-induced osteoclastogenesis and did not affect Wnt5a-induced Rank expression.

Conclusions:

• Wnt16 inhibits osteoclastogenesis but not osteoclast function.
• Wnt16's role in bone resorption is modulated by Wnt5a, indicating a complex regulatory mechanism.
• These findings highlight Wnt16 as a key inhibitory Wnt ligand in osteoclastogenesis, interacting with Wnt5a to control bone resorption.