Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH)

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...

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Bibliographic Details
Published in:	Biomolecules (Basel, Switzerland) Vol. 13; no. 10; p. 1553
Main Authors:	Hecht, Jacqueline T, Veerisetty, Alka C, Patra, Debabrata, Hossain, Mohammad G, Chiu, Frankie, Mobed, Claire, Gannon, Francis H, Posey, Karen L
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-10-2023 MDPI
Subjects:	Age Animals Antibodies Antigens Arthralgia Autophagy Care and treatment Cartilage Cartilage oligomeric matrix protein chondrocyte Chondrocytes Collagen COMP Degeneration Dosage and administration Drinking water Drug therapy dwarfism Endoplasmic reticulum Extracellular matrix Genetic aspects Inflammation Joints Laboratory animals Matrix protein Mice Mutants Mutation Nonsteroidal anti-inflammatory drugs Osteoarthritis Oxidative stress Pain Pathology Physiological aspects Protein folding Proteins Pseudoachondroplasia Resveratrol Resveratrol - pharmacology Resveratrol - therapeutic use United States United States > US COMP articular cartilage autophagy chondrocyte cartilage oligomeric matrix protein dwarfism joint pain joint degeneration resveratrol
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2218-273X 2218-273X
DOI:	10.3390/biom13101553