Cartilaginous repair of full-thickness articular cartilage defects is induced by the intermittent activation of PTH/PTHrP signaling

Objective: We studied the effects of the transient activation of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) signaling during the repair of 5-mm-diameter full-thickness defects of articular cartilage in the rabbit. Materials and methods: Cylindrical full-thickness articular cartilage defects of 5 mm in diameter were artificially created in the femoral trochlea of male adolescent Japanese white rabbits using a hand-drill. Recombinant human PTH(1-84) was then administered into the joint cavity continuously or intermittently for 2 weeks post-injury. The reparative tissues were histologically examined at 2, 4, and 8 weeks, and were also immunohistochemically examined for type II collagen. Double immunostaining analysis was also performed for the PTH/PTHrP receptor and proliferating cell nuclear antigen (PCNA) in the regenerating tissues. Results: No evidence of cartilage formation was evident throughout the period of the experiments in injured animals administered saline alone. In contrast, cartilage formation occurred at 4 weeks in both the continuous and intermittent PTH-treated defects. At 8 weeks post-injury, for the intermittently treated defects, the regenerated cartilage successfully resurfaced the defects and the original bone-articular cartilage junction was recovered. In contrast, the defects were covered with fibrous or fibrocartilaginous tissues in the continuously administered group. PCNA and PTH/PTHrP receptor-double positive mesenchymal cells were significantly increased in both the continuous and intermittent PTH-treated defects at 2 weeks post-injury. Conclusions: The present results suggest that the transient activation and release from PTH/PTHrP signaling during the early stages of the cartilage repair process facilitates the induction of regenerative chondrogenesis in full-thickness articular cartilage defects. (C) 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved,