PPARγ is involved in the hyperglycemia‐induced inflammatory responses and collagen degradation in human chondrocytes and diabetic mouse cartilages

Abstract

Diabetic hyperglycemia has been suggested to play a role in osteoarthritis. Peroxisome proliferator-activated receptor-g (PPARg) was implicated in several pathological conditions including diabetes and inflammation. The detailed effects and mechanisms of hyperglycemia on cartilage damage still need to be clarified. Here, we investigated the role of PPARg in hyperglycemia-triggered chondrocyte/cartilage damages using a human chondrocyte culture model and a diabetic mouse model. Human chondrocytes were cultured and treated with high concentration of glucose (30 mM) to mimic hyperglycemia in the presence or absence of pioglitazone, a PPARg agonist. Streptozotocin (STZ) was used to induce mouse diabetes. Our data showed that high glucose induced the protein expressions of cyclooxygenase-2 (COX-2) and production of prostaglandin-E 2 (PGE 2 ), interleukin-6 (IL-6), and metalloproteinase-13 (MMP-13), but decreased the protein expression of collagen II and PPARg in human chondrocytes. These alterations in high glucosetreated human chondrocytes could be reversed by pioglitazone in a dose-dependent manner. Moreover, pioglitazone administration could also significantly reverse the hyperglycemia, formation of AGEs, productions of IL-6 and MMP-13, and cartilage damage in STZinduced diabetic mice. Taken together, these findings suggest that hyperglycemia down-regulates PPARg expression and induces inflammatory and catabolic responses in human chondrocytes and diabetic mouse cartilages. Keywords: PPARg; diabetes; osteoarthritis; chondrocyte; collagen Chondrocytes, which are the only cellular components of cartilage, are embedded in extensive extracellular matrix (ECM) and maintain equilibrium between anabolic and catabolic activities under normal physiological circumstances. 1,2 Cartilage damage is caused by the imbalance between catabolic and anabolic capacities of chondrocytes. Catabolic activities of chondrocytes are related to the elevated release of cartilage degrading enzymes, such as matrix metalloproteinases (MMPs), while anabolic activities result in the productions of type II collagen and aggrecan. 3 MMPs are usually minimally expressed in normal physiological conditions while are highly induced under special pathological conditions, such as inflammation or arthritis. [4][5][6] In the joint cartilage, MMPs, synthesized and secreted by the residing chondrocytes, play a role in degrading ECM. 6 MMP-13 (collagenase-3) actively degrades type II collagen, which is a major collagen type related to build up the structural backbone of ECM in the cartilage. 7,8 Osteoarthritis (OA), one of the most common forms of arthritis diseases, is a progressive degenerative joint disease with signs and symptoms of inflammation, leading to significant functional impairment and disability in older adults. Growing evidence indicates that metabolic factors play a key role in the progression of arthritis diseases. 9 OA has recently been suggested to have a positive correlation with glucose imbalance, metabolic dysfunction, and diabe...

Hyperglycemia and Hyperinsulinemia-Like Conditions Independently Induce Inflammatory Responses in Human Chondrocytes

“…In summary, the results presented here, along with the pro-catabolic and anti-anabolic effects that we and others reported previously [11,12], further support the hypothesis that hyperglycemia per se can drive cartilage damage and OA, in agreement with in vivo studies that showed increased joint damage associated with a more intense inflammatory response in animal models of DM2 [13,14]. Moreover, the results obtained also indicate that hyperinsulinemia, which is characteristic of DM2 and metabolic syndrome, can also by itself contribute to activate an inflammatory state in human chondrocytes that can accelerate OA development and progression.…”

“…Only a few studies have been conducted so far to identify direct effects of high glucose in articular chondrocytes, collectively indicating that hyperglycemia-like glucose concentrations favor catabolic processes and impair anabolic responses [9][10][11][12][13], especially in chondrocytes from OA/aged articular cartilage [11,12]. Moreover, high glucose has also been shown to directly induce the expression of interleukin (IL)-6 and cyclooxygenase 2 [13], two important inflammatory mediators, as well as to potentiate the same inflammatory responses induced by interleukin-1β (IL-1β) [14].…”

“…Moreover, high glucose has also been shown to directly induce the expression of interleukin (IL)-6 and cyclooxygenase 2 [13], two important inflammatory mediators, as well as to potentiate the same inflammatory responses induced by interleukin-1β (IL-1β) [14].…”

Role of PPARα in down-regulating AGE-induced TGF-β and MMP-9 expressions in chondrocytes

“…Previous studies have discovered a close association between peroxisome proliferatoractivated receptor (PPAR) and the pathogenic mechanism of osteoarthritis (Lee et al, 2012;Rahigude et al, 2012;Chen et al, 2015). Thiazolidinediones such as pioglitazone, rosiglitazone, and troglitazone are the major synthetic ligands of PPARα that have found clinical application (Mahali et al, 2014).…”

Osteoarthritis and type 2 diabetes: From pathogenetic factors to therapeutic intervention

“…Moreover, synovial inflammation upregulates the local production of catabolic enzymes and, consequently, cartilage degradation . Past animal studies have shown that high blood glucose levels in diabetic rats were associated with a decrease of collagen and proteoglycans in articular cartilage and tendons, as well as with the deposition of collagen within the synovial membrane …”