A Retinoid Antagonist Attenuates Bone Growth Inhibition Caused by Growth Plate Injury in Mice

Abstract

Growth plate injury, which may trigger growth plate fusion or arrest, is a common occurrence in pediatric orthopaedics that can lead to angulation of the limb and limb length discrepancy. Growth plate injuries are currently treated palliatively, with surgical intervention when severe limb length discrepancy or angulation is found during follow-up visits. The cellular changes in the chondrocytes in injured growth plate have not been fully elucidated, and understanding these factors will provide important insights for the development of therapies that promote growth plate repair and prevent growth arrest. In this study, we refined a mouse growth plate injury model and demonstrated that needle-induced growth plate injury resulted in different healing outcomes depending on the size of the needle used. The 30G needle-induced injury was repaired without significant sequelae, while 25G injury induced bone bridge and limb length discrepancy. In the non-healing model, the growth plate showed severely reduced bone-forming activity rapidly after the injury, with a decreased number of osteoclasts in the chondro-osseous junction in the metaphysis. We found that the injured growth plate stimulated retinoid signaling evidenced by the upregulation of retinoid target molecules, and that treatment with 7C, a retinoic acid receptor gamma antagonist, ameliorated decreases in bone forming activity and osteoclast formation, and partially rescued injury-induced growth inhibition. The results of this study suggest that changes in the growth plate immediately post-injury should be considered as a therapeutic target for growth plate repair and that retinoid antagonists may be viable pharmacological interventions for this purpose.