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Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH).
Hecht, Jacqueline T; Veerisetty, Alka C; Patra, Debabrata; Hossain, Mohammad G; Chiu, Frankie; Mobed, Claire; Gannon, Francis H; Posey, Karen L.
Afiliación
  • Hecht JT; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
  • Veerisetty AC; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
  • Patra D; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Hossain MG; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
  • Chiu F; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
  • Mobed C; Department of Biology, Rice University, Houston, TX 77005, USA.
  • Gannon FH; Departments of Pathology and Immunology and Orthopedic Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
  • Posey KL; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
Biomolecules ; 13(10)2023 10 20.
Article en En | MEDLINE | ID: mdl-37892235
Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol's therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoartritis / Inflamación Límite: Animals Idioma: En Revista: Biomolecules Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoartritis / Inflamación Límite: Animals Idioma: En Revista: Biomolecules Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza