The zinc finger transcription factors Osr1 and Osr2 control synovial joint formation.

Synovial joints enable smooth articulations between different skeletal elements and are essential for the motility of vertebrates. Despite decades of extensive studies of the molecular and cellular mechanisms of limb and skeletal development, the molecular mechanisms governing synovial joint formation are still poorly understood. In particular, whereas several signaling pathways have been shown to play critical roles in joint maintenance, the mechanism controlling joint initiation is unknown. Here we report that Osr1 and Osr2, the mammalian homologs of the odd-skipped family of zinc finger transcription factors that are required for leg joint formation in Drosophila, are both strongly expressed in the developing synovial joint cells in mice. Whereas Osr1(-/-) mutant mice died at midgestation and Osr2(-/-) mutant mice had only subtle defects in synovial joint development, tissue-specific inactivation of Osr1 in the developing limb mesenchyme in Osr2(-/-) mutant mice caused fusion of multiple joints. We found that Osr1 and Osr2 function is required for maintenance of expression of signaling molecules critical for joint formation, including Gdf5, Wnt4 and Wnt9b. In addition, joint cells in the double mutants failed to upregulate expression of the articular cartilage marker gene Prg4. These data indicate that Osr1 and Osr2 function redundantly to control synovial joint formation.