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PTHrP buffers Wnt/β-catenin activity through a negative feedback loop to maintain articular cartilage homeostasis

Osteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. The Wnt/β-catenin cascade is essential in articular cartilage development and homeostasis. It has proved that both overexpression and loss of β-catenin lead to cartilage degeneration and OA symptoms. However, the mechanism of Wnt/β-catenin balance in healthy cartilage remains unclear. In the present work, we confirmed that the Wnt/β-catenin activation and PTHrP suppression in cartilage during the post-traumatic OA process. Then, we demonstrated that Wnt/β-catenin upregulated PTHrP expression through binding to its promoter (P2), and induce mRNA (AT6) transcript expression, while PTHrP repressed Wnt/β-catenin activity, and formed a Wnt/β-catenin-PTHrP negative feedback loop in the very primary chondrocytes to maintain cartilage homeostasis. However, this negative feedback loop vanished in dedifferentiated chondrocytes, hypertrophic chondrocytes, and IL-1β treated very primary chondrocytes. We further found that miR-106b-5p was increased in these “aberrant” chondrocytes and directly targeted PTHrP mRNA to abolish the feedback loop. PKC-ζ was activated by PTHrP through phosphorylation at Thr410/403, and subsequently induced β-catenin phosphorylation and ubiquitination. Finally, we disclosed that exogenous PTHrP attenuated OA progression exogenous PTHrP attenuated OA progression. Together, these findings reveal that PTHrP is a vital mediator to keep Wnt/β-catenin activity homeostasis in healthy cartilage through a negative feedback loop, and PTHrP might be a therapeutic target for OA and cartilage regeneration.