High‐fat diet induces endoplasmic reticulum stress to promote chondrocyte apoptosis in mouse knee joints

Abstract

Mice fed a high‐fat diet (HFD) become obese and develop osteoarthritis (OA)‐like lesions, including chondrocyte apoptosis, in the knee joints. However, the mechanism by which HFD/obesity induces chondrocyte apoptosis is not clearly understood. In the present study, male mice were fed a low‐fat diet (LFD, 10% kcal), HFD (45% kcal), or a HFD administered with 0.5 g/kg bodyweight of 4‐phenyl butyric acid (PBA, a small chaperone known to ease endoplasmic reticulum [ER] stress), via the drinking water. At the end of the 18‐week study, stifle (knee) joints from all animals were collected, fixed, paraffin embedded, and sectioned. Immunostaining of joints from the HFD group showed increased expression of ER stress and apoptotic markers and increased expression of nuclear protein 1 and tribbles related protein‐3 compared to the LFD group. Mice on HFD also showed higher percentage of chondrocyte death, lower chondrocyte numbers per cartilage area, and thickening of subchondral bone. Administration of PBA alleviated all of the HFD‐induced symptoms. Our study demonstrated that HFD induces ER stress to promote chondrocyte death and subchondral bone thickening, which could be relieved by alleviating ER stress via PBA administration, suggesting that ER stress could play an important role in obesity‐linked OA and could be targeted for OA therapeutics.

Curcumin-Alleviated Osteoarthritic Progression in Rats Fed a High-Fat Diet by Inhibiting Apoptosis and Activating Autophagy via Modulation of MicroRNA-34a

“… 38 , 39 Our histological and behavioral observations confirmed that rats fed a HFD presented OA-like lesions, consistent with our previous and others’ studies. 40 , 41 Previously, oral administration of curcumin was shown to be effective in slowing the progression of OA in a post-traumatic OA mouse model. 42 However, doubts have been raised regarding whether oral curcumin can reach pharmacologically active concentrations in synovial fluid or joint tissues 43 and the oral bioavailability of curcumin is only 1%.…”

Potential of miR-25-3p in protection of chondrocytes: emphasis on osteoarthritis

“…OA, typified by joint space narrowing and a degenerative loss of cartilage integrity, is a dominant reason for disability, pain, and shortening of adult working life [17]. Interestingly, there is evidence showing that apoptosis is progressively recognized as a crucial driver of OA cartilage pathology [18,19]. Dysregulated gene expression in chondrocytes is implicated in the apoptosis and proliferation of chondrocytes, emphasizing the functional role of miRNAs in controlling chondrocyte apoptosis and development of OA [9,20].…”

Regulating metabolic inflammation by nutritional modulation

“…40 More recently, HFD-induced obesity has been shown to induce osteoarthritis-promoting ER stress in mice, further highlighting the importance of considering the contribution of ER stress to the progression of metaflammation in the context of obesity. 41 Consistent with these discoveries, a significant increase in ER stress markers associated with adipose tissue inflammation appears in mice after 16 weeks of an HFD, which can be reversed by the administration of chemical chaperons. 42 Indeed, ER stress is known to induce the activation of the unfolded protein response (UPR), which aims at restoring cell function and production of adequatly folded proteins by using chaperons.…”