Effects of Hyaluronic Acid on Mitochondrial Function and Mitochondria-driven Apoptosis following Oxidative Stress in Human Chondrocytes

Abstract

Hyaluronic acid is widely used in the treatment of osteoarthritis and exerts significant chondroprotective effects. The exact mechanisms of its chondroprotective action are not yet fully elucidated. Human articular chondrocytes actively produce reactive oxygen and nitrogen species capable of causing cellular dysfunction and death. A growing body of evidence indicates that mitochondrial dysfunction and mitochondrial DNA damage play a causal role in disorders linked to excessive generation of oxygen free radicals. We hypothesized that the chondroprotective effects of hyaluronic acid on oxidatively stressed chondrocytes are due to preservation of mitochondrial function and amelioration of mitochondria-driven apoptosis. When primary human chondrocyte cultures were exposed to reactive oxygen or nitrogen species generators, mitochondrial DNA damage along with mitochondrial dysfunction and mitochondria-driven apoptosis accumulated as a consequence. In addition, cytokinetreated primary human chondrocytes showed increased levels of mitochondrial DNA damage. Pretreatment of chondrocytes with hyaluronic acid caused a decrease of mitochondrial DNA damage, enhanced mitochondrial DNA repair capacity and cell viability, preservation of ATP levels, and amelioration of apoptosis. The results of these studies demonstrate that enhanced chondrocyte survival and improved mitochondrial function under conditions of oxidative injury are probably important therapeutic mechanisms for the actions of hyaluronic acid in osteoarthritis.

Adverse Effects of Antimicrobials via Predictable or Idiosyncratic Inhibition of Host Mitochondrial Components

“…Hyaluronic acid, which is essential for the maintenance of synovial joints, has recently been shown to have a protective effect for radical-induced mitochondrial DNA damage (25). In this scenario, hyaluronic acid may be utilized by mitochondria damaged by fluoroquinolone exposure, thereby creating a shortage of hyaluronic acid at the articular surface of the joint.…”

Hyaluronan suppresses lidocaine-induced apoptosis of human chondrocytes in vitro by inhibiting the p53-dependent mitochondrial apoptotic pathway

“…Hyaluronan is an essential component of the extracellular matrix and is involved in important physiological functions, such as cell-to-cell identification, cellular cohesion, growth regulation, and antioxidant capacity [14] . Its combination with LAs may also ameliorate apoptotic cell death and enhance cell survival in chondrocytes [15,16] . However, the precise mechanisms of hyaluronan actions, especially those associated with cytoprotection, have not been firmly established, despite its widespread use in outpatient clinics.…”

Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes

“…Moreover, that study also showed that OA chondrocytes exposed to a high, hyperglycemia-like extracellular glucose concentration (30 mM) were unable to reduce glucose transport and GLUT-1 content which led to increased glucose accumulation and prolonged Reactive Oxygen Species (ROS) production [Rosa et al, 2009]. Increased oxidative stress has been pointed out as a major pathogenic mechanism of OA [Maneiro et al, 2003;Grishko et al, 2009], and at the cellular level, increased ROS production has been shown to mediate many catabolic responses in chondrocytes [Lo et al, 1998; Mendes et al, 2003a,b].…”

“…Moreover, that study also showed that OA chondrocytes exposed to a high, hyperglycemia-like extracellular glucose concentration (30 mM) were unable to reduce glucose transport and GLUT-1 content which led to increased glucose accumulation and prolonged Reactive Oxygen Species (ROS) production [Rosa et al, 2009]. Increased oxidative stress has been pointed out as a major pathogenic mechanism of OA [Maneiro et al, 2003;Grishko et al, 2009], and at the cellular level, increased ROS production has been shown to mediate many catabolic responses in chondrocytes [Lo et al, 1998; Mendes et al, 2003a,b].Thus, this study was undertaken to determine whether exposure to a high extracellular glucose concentration can shift normal and OA chondrocyte functions towards a pro-catabolic and/or antianabolic gene expression profile, either direct or indirectly by modifying the responses induced by pro-anabolic stimuli, namely TGF.For this purpose, we examined by real time RT-PCR (qRT-PCR) the expression of genes that are important for cartilage homeostasis and OA pathogenesis and that in other cell types have been reported to be modulated by exposure to high glucose [Death et al, 2003;Ho et al, 2007;Andreea et al, 2008;Kim et al, 2008]. Those genes include the MMPs-1 and -13 due to their major role in cartilage matrix degradation, and collagen type II, TIMP-1 and TIMP-2 as important anabolic and anti-catabolic genes, respectively.…”