Regulation of osteoclast function via Rho-Pkn3-c-Src pathways.

Area of Science:

• Cell Biology
• Molecular Biology
• Bone Biology

Background:

• Wnt signaling pathways are crucial in bone metabolism, with canonical and non-canonical pathways having distinct roles.
• Previous research indicated Wnt5a-receptor tyrosine kinase-like orphan receptor 2 (Ror2) signaling promotes osteoclast differentiation.
• The precise function of Wnt5a-Ror2 signaling in mature osteoclast activity remained undetermined.

Purpose of the Study:

• To elucidate the role of Wnt5a-Ror2 signaling in osteoclast function and bone resorption.
• To identify downstream effectors and molecular mechanisms involved in Wnt5a-Ror2-mediated osteoclast activity.

Main Methods:

• Utilized osteoclast-specific Ror2-deficient mice (Ror2ΔOCL/ΔOCL) and protein kinase N3 (Pkn3)-deficient mice.
• Investigated the activation of Rho and its downstream effectors, including Pkn3, in osteoclasts.
• Analyzed the interaction of Pkn3 with c-Src and Pyk2 and its impact on kinase activity.

Main Results:

• Osteoclast-specific Ror2 deficiency led to increased trabecular bone mass due to reduced osteoclast bone-resorbing activity.
• Wnt5a-Ror2 signaling activated Rho via dishevelled-associated activator of morphogenesis 2 (Daam2) in osteoclasts.
• Pkn3 expression increased during osteoclast differentiation, and Pkn3 deficiency also resulted in greater trabecular bone mass.
• Pkn3 directly bound to c-Src and Pyk2, enhancing c-Src kinase activity in a Wnt5a-Ror2-dependent manner, which is essential for osteoclast bone resorption.

Conclusions:

• Wnt5a-Ror2 signaling stimulates osteoclast bone-resorbing activity through the Daam2-Rho-Pkn3-c-Src pathway.
• Pkn3 is a key mediator in Wnt5a-Ror2 signaling's effect on osteoclast function.
• Targeting Pkn3 presents a potential therapeutic strategy for osteoporosis and inflammatory bone diseases.