SHP2 ablation mitigates osteoarthritic cartilage degeneration by promoting chondrocyte anabolism through SOX9.

Autor: Wang L; Department of Orthopaedic Surgery, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA., Yang H; Department of Orthopaedic Surgery, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA., Wang C; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA., Wang M; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA., Huang J; Department of Orthopaedic Surgery, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA., Nyunt T; Department of Orthopaedic Surgery, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA., Osorio C; Department of Orthopaedic Surgery, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA., Sun SY; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Pacifici M; Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Lefebvre V; Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Moore DC; Department of Orthopaedic Surgery, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA., Wang S; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA., Yang W; Department of Orthopaedic Surgery, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Sep 15; Vol. 38 (17), pp. e70013.
DOI: 10.1096/fj.202400642R
Abstrakt: Articular cartilage phenotypic homeostasis is crucial for life-long joint function, but the underlying cellular and molecular mechanisms governing chondrocyte stability remain poorly understood. Here, we show that the protein tyrosine phosphatase SHP2 is differentially expressed in articular cartilage (AC) and growth plate cartilage (GPC) and that it negatively regulates cell proliferation and cartilage phenotypic program. Postnatal SHP2 deletion in Prg4 + AC chondrocytes increased articular cellularity and thickness, whereas SHP2 deletion in Acan + pan-chondrocytes caused excessive GPC chondrocyte proliferation and led to joint malformation post-puberty. These observations were verified in mice and in cultured chondrocytes following treatment with the SHP2 PROTAC inhibitor SHP2D26. Further mechanistic studies indicated that SHP2 negatively regulates SOX9 stability and transcriptional activity by influencing SOX9 phosphorylation and promoting its proteasome degradation. In contrast to published work, SHP2 ablation in chondrocytes did not impact IL-1-evoked inflammation responses, and SHP2's negative regulation of SOX9 could be curtailed by genetic or chemical SHP2 inhibition, suggesting that manipulating SHP2 signaling has translational potential for diseases of cartilage dyshomeostasis.
(© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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