Molecular and Cellular Effects of Chemical Chaperone—TUDCA on ER-Stressed NHAC-kn Human Articular Chondrocytes Cultured in Normoxic and Hypoxic Conditions

Abstract

Osteoarthritis (OA) is considered one of the most common arthritic diseases characterized by progressive degradation and abnormal remodeling of articular cartilage. Potential therapeutics for OA aim at restoring proper chondrocyte functioning and inhibiting apoptosis. Previous studies have demonstrated that tauroursodeoxycholic acid (TUDCA) showed anti-inflammatory and anti-apoptotic activity in many models of various diseases, acting mainly via alleviation of endoplasmic reticulum (ER) stress. However, little is known about cytoprotective effects of TUDCA on chondrocyte cells. The present study was designed to evaluate potential effects of TUDCA on interleukin-1β (IL-1β) and tunicamycin (TNC)-stimulated NHAC-kn chondrocytes cultured in normoxic and hypoxic conditions. Our results showed that TUDCA alleviated ER stress in TNC-treated chondrocytes, as demonstrated by reduced CHOP expression; however, it was not effective enough to prevent apoptosis of NHAC-kn cells in either normoxia nor hypoxia. However, co-treatment with TUDCA alleviated inflammatory response induced by IL-1β, as shown by down regulation of Il-1β, Il-6, Il-8 and Cox2, and increased the expression of antioxidant enzyme Sod2. Additionally, TUDCA enhanced Col IIα expression in IL-1β- and TNC-stimulated cells, but only in normoxic conditions. Altogether, these results suggest that although TUDCA may display chondoprotective potential in ER-stressed cells, further analyses are still necessary to fully confirm its possible recommendation as potential candidate in OA therapy.

Discovery of Taurocholic Acid Sodium Hydrate as a Novel Repurposing Drug for Intervertebral Disc Degeneration by Targeting MAPK3

“…found that ursodeoxycholic acid, a hydrophilic bile acid, which has antioxidant and anti‐inflammatory activities, could induce bone regeneration via stimulating the osteogenic differentiation of MSCs 22 . Additionally, tauroursodeoxycholic acid was identified as a potential candidate for osteoarthritis by its chondroprotective 23,24 . In this study, we found a small molecular compound of bile acid family, NAT, which could enhance expression of COL2A1 and OCN both in vivo and in vitro , ameliorate the secondary osteoporosis, and delay the development of IDD.…”

“…22 Additionally, tauroursodeoxycholic acid was identified as a potential candidate for osteoarthritis by its chondroprotective. 23,24 In this study, we found a small molecular compound of bile acid family, NAT, which could enhance expression of COL2A1 and OCN both in vivo and in vitro, ameliorate the secondary osteoporosis, and delay the development of IDD. Moreover, we confirmed that a low dose of NAT showed major impact on osteoblasts differentiation.…”

Salicin modifies osteoarthritis progression by binding on IRE1α and inhibiting IRE1α mediated endoplasmic reticulum stress

“…Meanwhile, it is widely accepted that ER stress is directly associated with chondrocytes apoptosis and death [38][39][40] . What's more, recent studies confirmed OA inflammation is also related to ER stress [41][42][43][44][45] . Be similar with these obtained conclusions, we found by directly bound with IRE1α, SA inhibited IRE1α mediated ER stress and subsequently promotes chondrocytes proliferation, decreases inflammatory factors expression and inhibits chondrocytes apoptosis.…”

The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway

“…It is widely accepted that ER stress is directly associated with chondrocyte apoptosis and death [48][49][50] . Moreover, recent studies have confirmed that OA inflammation is related to ER stress [51][52][53][54][55] . In this study, we first detected the expression levels of PERK, p-PERK, IRE1α, p-IRE1α, and AFT6 after stimulation with TNF-α in the presence of SA and found that SA did not influence TNF-α-induced PERK phosphorylation or ATF6 expression.…”