Research ArticlePhysiology

Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling

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Sci. Signal.  29 Aug 2017:
Vol. 10, Issue 494, eaan0023
DOI: 10.1126/scisignal.aan0023

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Bone breakdown

To resorb bone, osteoclasts must remodel the cytoskeleton to form actin rings. Thus, understanding the pathways that control actin ring formation in osteoclasts could reveal potential therapeutic targets for reversing losses in bone density in diseases such as osteoporosis. Using genetically manipulated mice and cells derived from these mice, Uehara et al. characterized a pathway that stimulated bone resorption by osteoclasts. Binding of Wnt5a to one of its receptors, Ror2, activated the small GTPase Rho, its effector Pkn3, and c-Src, a kinase that is required for actin ring formation. The authors note that several of these proteins are implicated in tumor metastasis and that this signaling pathway may operate in metastasizing cancer cells.

Abstract

Cytoskeletal reorganization in osteoclasts to form actin rings is necessary for these cells to attach to bone and resorb bone matrices. We delineated the pathway through which Wnt5a signaling through receptor tyrosine kinase–like orphan receptor 2 (Ror2) promoted the bone-resorbing activity of osteoclasts. Wnt5a binding to Ror2 stimulated Rho, a small GTPase involved in cytoskeletal reorganization. Subsequently, the Rho effector kinase Pkn3 bound to and enhanced the activity of c-Src, a nonreceptor tyrosine kinase that is critical for actin ring formation. Mice with an osteoclast-specific deficiency in Ror2 (Ror2ΔOcl/ΔOcl) had increased bone mass. Osteoclasts derived from these mice exhibited impaired bone resorption and actin ring formation, defects that were rescued by overexpression of constitutively active RhoA. These osteoclasts also exhibited reduced interaction between c-Src and Pkn3 and reduced c-Src kinase activity. Similar to Ror2ΔOcl/ΔOcl mice, mice with a global deficiency of Pkn3 (Pkn3−/−) had increased bone mass. The proline-rich region and kinase domain of Pkn3 were required to restore the bone-resorbing activity of osteoclasts derived from Pkn3−/− mice. Thus, Pkn3 promotes bone resorption downstream of Wnt5a-Ror2-Rho signaling, and this pathway may be a therapeutic target for bone diseases such as osteoporosis, rheumatoid arthritis, and periodontal disease.

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