Role of noncanonical Wnt ligands and Ror-family receptor tyrosine kinases in the development, regeneration, and diseases of the musculoskeletal system.

The Ror-family receptor tyrosine kinases (RTKs), consisting of Ror1 and Ror2, play crucial roles in morphogenesis and formation of various tissues/organs, including the bones and skeletal muscles, the so-called musculoskeletal system, during embryonic development, by acting as receptors or coreceptors for a noncanonical Wnt protein Wnt5a. Furthermore, several lines of evidence have indicated that Ror1 and/or Ror2 play critical roles in the regeneration and maintenance of the musculoskeletal system in adults. Considering the anatomical and functional relationship between the skeleton and skeletal muscles, their structural and functional association might be tightly regulated during their embryonic development, development after birth, and their regeneration after injury in adults. Importantly, in addition to their congenital anomalies, much attention has been paid onto the age-related disorders of the musculoskeletal system, including osteopenia and sarcopenia, which affect severely the quality of life. In this article, we overview recent advances in our understanding of the roles of Ror1- and/or Ror2-mediated signaling in the embryonic development, regeneration in adults, and congenital and age-related disorders of the musculoskeletal system and discuss possible therapeutic approaches to locomotive syndromes by modulating Ror1- and/or Ror2-mediated signaling.