Impaired autophagy contributes to the aggravated deterioration of osteoarthritis articular cartilage by peroxisome proliferator-activated receptor a deficiency, associated with decreased ERK and Akt activation

Background Although the chondroprotection of peroxisome proliferator-activated receptor a (PPAR alpha) activation against osteoarthritis (OA) has been revealed, the regulatory mechanism of PPAR alpha deficiency to aggravate osteoarthritic cartilage deterioration remains unclear. Here, we aimed to investigate whether and how autophagy is involved in OA pathological progression. Methods Model of experimental OA was established using destabilization of the medial meniscus in PPAR alpha-KO 129S4/SvJae male mice, followed by histopathological detection of articular cartilage and immunohistochemistry detection of extracellular matrix (ECM) or autophagy-related signal molecules. Meanwhile, human OA chondrocytes obtained from total knee replacement surgery patients with OA were cultured with the pretreatment of IL-1 beta, followed with the treatment of PPAR alpha agonist WY14643 and the detection of related signal molecules. Results PPAR alpha deficiency aggravated cartilage damage with decreased LC3B level in combination with an increase in P62 level, accompanied with reduced p-Akt and p-ERK levels in PPAR alpha-KO mouse model of experimental OA. On the contrary, PPAR alpha activation by WY14643 promoted ECM synthesis in IL-1 beta-treated human OA chondrocytes, accompanied with increased LC3B-II/I ratio and Beclin 1 level and decreased P62 and Bcl2 levels. Meanwhile, it was observed that activated ERK and Akt by PPARa activation contributed to the enhancement of autophagy and ECM synthesis in human OA chondrocytes. Conclusions Impaired autophagy contributed to the aggravated deterioration of osteoarthritis articular cartilage by PPARa deficiency associated with the suppression of ERK and Akt, with an implication that triggering PPAR alpha activation ought to be a potential promising therapeutic target for OA therapy.

Automated summary

This study revealed that PPARα deficiency aggravates cartilage damage in osteoarthritis and is associated with impaired autophagy and suppression of ERK and Akt. Activation of PPARα promotes autophagy and extracellular matrix synthesis in human OA chondrocytes. Therefore, triggering PPARα activation could be a potential therapeutic target for OA therapy.