Abstract
Obesity, a major risk factor for the development of osteoarthritis (OA), is associated with increased circulating levels of free fatty acids (FFA). However, the role of these FFAs in OA pathophysiology is not clearly understood. In the present study, we found that palmitate treatment of human primary articular chondrocytes increased the expression of ER stress markers [activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP)] and apoptosis markers [cytochrome c and cleaved caspase-3 (CC3)]. Palmitate treatment also increased the expression of Nuclear protein 1 (Nupr1) and tribbles related protein 3 (TRB3), which are known negative regulators of cell survival pathways. Knockdown of Nupr1 or CHOP expression inhibited palmitate mediated increased expression of TRB3 and CC3, indicating that Nupr1 and CHOP cooperate to regulate cell survival and apoptotic pathways in human chondrocytes. Nupr1 knockdown had no effect on CHOP expression whereas CHOP knockdown abolished the palmitate-mediated Nupr1 expression, indicating that CHOP is functional upstream to Nupr1 in this pathway. Moreover, overexpression of Nupr1 markedly increased the basal expression of pro-apoptotic molecules, including cytochrome c and CC3. Taken together, our study demonstrates that Nupr1 plays a crucial role in palmitate-induced apoptosis in human chondrocytes and Nupr1 as a potential novel drug target for the treatment of OA.
Highlights
Osteoarthritis (OA) is the most common type of arthritis and one of the leading causes of global disability, affecting approximately 300 million people worldwide [1]
Treatment of normal human articular chondrocytes with palmitate, but not oleate, increased the expressions of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) (Figure 1A,B and Supplementary Figure S1A) that are markers for endoplasmic reticulum (ER) stress, and cytochrome c as well as cleaved caspase-3 (CC3) (Figure 1A and Supplementary Figure S1B,C), which are markers for apoptosis
Our results imply that both Nuclear protein 1 (Nupr1) and tribbles related protein 3 (TRB3) are involved in palmitate-induced apoptosis in human articular chondrocytes
Summary
Osteoarthritis (OA) is the most common type of arthritis and one of the leading causes of global disability, affecting approximately 300 million people worldwide [1]. OA is characterized by progressive loss of articular cartilage due to abnormal anabolic and catabolic activities of chondrocytes [2,3]. Increased levels of FFA in synovial fluid and in the joint tissue are associated with increased severity of cartilage lesions in OA [6]. These studies clearly suggest that FFAs play an important role in OA pathophysiology. We recently demonstrated that palmitate induced endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) signaling pathway and promoted apoptosis in both meniscus and articular chondrocytes [8,9]. The molecular mechanisms underlying the effects of palmitate are still poorly understood
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