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

Wenxue Tong,Jiankun Xu, Qiuli Qi,Hongjiang Chen, Tao Huang, Chunxia Chen, Weiyang Liu,Zhonglian Huang,Youbin Chen,Zebin Ma, Di Zhao,Jun Hu

bioRxiv (Cold Spring Harbor Laboratory)(2022)

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摘要
AbstractOsteoarthritis (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.
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articular cartilage homeostasis,pthrp buffers wnt/β-catenin
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