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Inhibition of Chondrocyte Hypertrophy of Osteoarthritis by Disruptor Peptide

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Thomas Jefferson University Philadelphia United States

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The goal of this research project is to characterize how disruptor peptide blocks beta-catenin interaction with PTH receptor, and inhibits chondrocyte hypertrophy in vitro and in vivo. We designed a disruptor peptide corresponding to the carboxyl-terminal region of PTH receptor, and found this disruptor peptide inhibited beta-catenin binding to PTH receptor by GST-pull down assay. We also confirmed that disruptor peptide conjugated to penetratin can enter cells. Importantly, disruptor peptide reversed the beta-catenin-mediated PTH receptor signaling switch by increasing GscAMP signaling and inhibiting GqPLC activation in wild-type and beta-catenin knockout cells by using CRISPRCas9 genome-editing technology. In addition, the disruptor peptide enhanced PTHrP stimulated chondrogenesis and promoted PTHrP-inhibited chondrocyte hypertrophy. Furthermore, in mouse osteoarthritis model surgically induced by destabilization of the medial meniscus, articular-injection of PTHrP inhibited both type X collagen hypertrophic marker and matrix metalloproteinase 13 catabolic enzyme. These data suggest that the disruptor peptide favors the therapeutic signaling arm and improves the ability of PTHrP to inhibit cartilage degeneration and treatprevent osteoarthritis.

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Technical Report,01 Jul 2016,31 Dec 2018



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Approved For Public Release;

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