Canonical Wnt-inhibition Ameliorates TMJ Pathology in a Rabbit TMJ Injury Model

Abstract

Introduction: Loss of TMJ tissue due to injury or chronic degeneration can lead to TMJ dysfunction and severe pain. Current treatment modalities for TMJ injury/ degeneration are limited and there are no biological treatments that regenerate TMJ tissues. Therefore the identification of TMJ progenitor cells (TMJ-PCs) that can be stimulated to regenerate damaged TMJ tissue could shed new light on the development of regenerative medicinal treatments for TMJ disease in humans. Our preliminary data demonstrate that the TMJ cartilage harbors progenitor cells that spontaneously undergo endochondral ossification; thus TMJ-PCs form de novo cartilage that undergoes terminal differentiation and eventually forms bone when transplanted in vivo. Our goal is to identify signaling pathways to manipulate TMJ-PCs to maintain cartilage for therapeutic applications. Canonical Wnt pathway is one signaling pathway that has been implicated in cartilage homeostasis by inhibiting early cartilage formation and promoting terminal chondrocyte differentiation [1]. Therefore blocking Wnt pathway via Wnt antagonists has been shown to promote chondrogenesis, the process of cartilage formation [1-4]. Our preliminary data demonstrate that one canonical Wnt antagonist, sclerostin (SOST), can promote TMJ-PCs to form cartilage. To test whether SOST can ameliorate cartilage damage in the TMJ in vivo, we have developed a surgical TMJ injury model in rabbits. Objective: We propose to determine the efficacy of sclerostin, a canonical Wnt inhibitor, in promoting cartilage regeneration and preventing degeneration in a rabbit TMJ injury model. Methods: 3-4 month-old New Zealand white rabbits were subjected to bilateral TMJ disc perforation. After each rabbit was anesthetized, the pre-auricular region of the rabbit was shaved and prepped under sterile conditions. To surgically access the superior joint space, a 1-2 cm incision was made along the lateral upper border of the zygomatic arch to directly expose the TMJ disc. A punch biopsy was used to create a 2.5 mm perforation in the TMJ disc bilaterally. Sham surgery was performed on the contralateral side. SOST was injected into the TMJ space unilaterally weekly for 8 weeks. PBS was injected on the contralateral side as a negative control. Gross pathological and histological evaluation were performed on the rabbit TMJ condyles 8 weeks postoperatively. Results: Treatment of condyles with sclerostin was shown to visually reduce inflammation, fibrosis, and osteoarthritic pathogenesis in the TMJ condyle.