Osteoarthritis and Oxidative Stress

Among the chronic rheumatic diseases, hip and knee osteoarthritis (OA) is the most prevalent and is a leading cause of pain and disability in most countries worldwide. Its prevalence increases with age and generally affects women more frequently than men. OA is strongly associated with aging and heavy physical occupational activity, a required livelihood for many people living in rural communities in developing countries. Determining region-specific OA prevalence and risk factor profiles will provide important information for planning future cost effective preventive strategies and health care services.

Osteoarthritis (OA) is a chronic degenerative disorder of multifactorial etiology characterized by the loss of articular cartilage, hypertrophy of bone at the margins, subchondral sclerosis, and range of biochemical and morphological alterations of the synovial membrane and joint capsule.

Pathological changes in the late stage of OA include softening, ulceration, and focal disintegration of the articular cartilage. Synovial inflammation also may occur. Typical clinical symptoms are pain, particularly after prolonged activity and weight-bearing; whereas stiffness is experienced after inactivity. It is probably not a single disease but represents the final end result of various disorders leading to joint failure. It is also known as degenerative arthritis, which commonly affects the hands, feet, spine, and large weight-bearing joints, such as the hips and knees.

Most cases of OA have no known cause and are referred to as primary OA. Primary osteoarthritis is mostly related to aging. It can present as localized, generalized, or as erosive OA. Secondary osteoarthritis is caused by another disease or condition.

Osteoarthritis is the second most common rheumatologic problem and it is the most frequent joint disease with a prevalence of 22% to 39% in India. OA is more common in women than men, but the prevalence increases dramatically with age. Nearly, 45% of women over the age of 65 years have symptoms while radiological evidence is found in 70% of those over 65 years. OA of the knee is a major cause of mobility impairment, particularly among females. OA was estimated to be the 10th leading cause of nonfatal burden.

Self report surveys may not accurately estimate OA as there could be unknown cases in the community. There are few studies of OA that have used a radiological classification of disease. X-ray findings do not always match symptoms, but prevalence based on radiography is probably a reasonable population estimate. OA of the knee is more prevalent as per the literature available.

Therefore, for finding the current burden of OA and its association with lifestyle related factors, it was essential to undertake such a study on the prevalence of knee OA in Indian population.

Osteoarthritis (OA) is a complex disorder of unknown etiology that affects many different joints, being a major cause of disability in the general population. It is characterized by morphological, biochemical, molecular and biomechanical changes of both cells and extracellular matrix (ECM) which lead to softening, fibrillation, ulceration, loss of articular cartilage, synovial inflammation, sclerosis of subchondral bone, formation of osteophytes and subchondral cysts. OA is a multifactorial and polygenic disease and its pathogenesis is influenced by several genetic and environmental factors associated with the activation of molecular pathways that contribute to the progression of articular injury. Further understanding of these molecular pathways and their interactions with the different joint tissues is needed to develop new approaches for the prevention and treatment of OA. Recent studies have concluded that OA progression is significantly related to oxidative stress and reactive oxygen species (ROS). The present review aims at unraveling the contribution of the oxidative stress signaling pathway to OA pathobiology and summarizing potential therapeutic strategies to target this pathway.

ROS are free radicals containing oxygen molecules including hydroxyl radical (OH−), hydrogen peroxide (H2O2), superoxide anion (O2−), nitric oxide (NO) and hypochlorite ion (OCl−). The presence of unpaired electrons in the valence shell causes ROS to be short-lived, unstable and highly reactive in order to achieve stability. The major sites of ROS generation include the mitochondria (through oxidative phosphorylation), non-mitochondrial membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and xanthine oxidase (XO). Of these, the most likely source is mitochondria: it is estimated that 2–3% of the total O2 consumed by functional mitochondrial electron transport chains is incompletely reduced to the O2−, rather than to water. The NADPH oxidase enzymes (NOXes) are the major sources of ROS in phagocytes through the reaction 2O2 + NADPH → 2O2− + NADP+ + H+. NADPH oxidase comprises 5 components: three cytosolic (p40phox, p47phox, p67phox) and two membranic (p22phox and gp91 phox). Upon stimulation, cytosolic components translocate to the inner face of the plasma membrane to form a fully active enzyme complex that possesses NADPH oxidase activity. A similar process is believed to take place in non-phagocytic cells as well. XO catalyzes the oxidation of hypoxanthine to xanthine, producing H2O2.

Extensive mechanisms for scavenging ROS have evolved in species that utilize oxygen for energy production. This antioxidant system includes enzymatic and non-enzymatic antioxidants, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidise (GPX), glutathione (GSH), NADPH ubiquinone oxidoreductase (NQO1), paraoxonases (PON), ascorbic acid (vitamin C), α-tocopherol (vitamin E) and carotinoids. They react spontaneously and scavenge many forms of ROS thus maintaining intracellular redox milieu. Oxidative stress has been defined as a disturbance in the balance between the production of ROS and antioxidant defenses which results in macromolecular damage and disruption of redox signaling and control.

The free radical NO is produced by a number of different cell types with a variety of biological functions. NO is a product of the oxidation of l-arginine to l-citrulline in a two step process catalyzed by the enzyme nitric oxide synthase (NOS). Three major isoforms of NOS have been identified. The constitutive isoforms found in neurons and endothelial cells, namely neuronal NOS (nNOS) and endothelial NOS (eNOS), produce very low amounts of NO in a calcium- and calmodulin-dependent fashion. The inducible isoform (iNOS), found in a variety of cells, is expressed for a longer period of time, requires minimal concentrations of calcium, produces NO in relatively large amounts in response to proinflammatory cytokines (LPS, IL-1, TNF-α, IFN-γ) and acts in a host defensive role through its oxidative toxicity. Regardless of the source/role, NO reacts with several different molecules that are normally present to form either nitrate (NO3−) or nitrite (NO2−). Reactive nitrogen species (RNS) are a family of molecules derived from NO and O2− acting with ROS to damage cells, causing nitrosative stress.

ROS have long been known to be a component of the killing response of immune cells to bacterial invasion. The stimulated production of ROS by phagocytic cells, catalyzed by NADPH oxidase, was originally called “the respiratory burst” because of the increased consumption of oxygen by these cells. Recent evidence have shown that ROS are produced in all cell types and serve as important cellular messengers in normal signal transduction, gene regulation and cell cycling. ROS-induced cell signaling involves two general mechanisms: alterations in the intracellular redox state and oxidative modification of proteins.

ROS-induced signaling comprise inhibition of tyrosine phosphatase leading to cell proliferation, translocation and activation of serine/threonine kinases, such as protein kinase C and tyrosine hydroxylase mRNA, activation of the mitogen-activated protein kinases (MAPKs), nuclear factor (NF)-κB, p53, activator protein (AP)-1 and lipid pathways [phospholipases, protein kinase C (PKC) and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway]. Another major mechanism for ROS redox signaling is the reversible oxidation of the sulfhydryl group (− SH) in the cysteine residue to form SOH, SO2H or SO3H derivatives which alter the activity of an enzyme if the cysteine is located in a catalytic domain or DNA-binding site. Because they can be readily reduced from Cys-SOH back to Cys-SH, the oxidation/reduction of protein thiols represents a reversible intermediate similar to the classic signaling intermediates created by phosphorylation/dephosphorylation of tyrosine, serine, or threonine residues. In the presence of excessive ROS, SOH can be further oxidized to SO2H and SO3H forms which may or may not be reduced back to SH. As an indirect mechanism of signaling pathways, ROS contribute to post-translational protein modification by forming intramolecular disulfide bridges in cysteine residues leading to change in the structure of protein kinases and reversible inactivation of phosphatases. Several proteins can also become cross-linked because of active dityrosine formation from two tyrosine molecules by H2O2 peroxidase-dependent reactions. H2O2 participates in the one-electron reaction with transition metal ions to generate various intermediate ferryl species which are powerful oxidating agents that can lead to lipid oxidation and DNA damage.

Cells respond to ROS in different ways depending on the intensity, duration and context of the signaling, and the cellular redox status. When the oxidant level does not exceed the reducing abilities of cells, ROS are involved in several physiological cellular functions including signal transmission. In contrast, in some pathological situations, when the cellular antioxidant capacity is insufficient to detoxify ROS, oxidative stress may occur and ROS react with DNA, proteins and lipids, disrupting their normal structure, impairing function and leading to cytotoxicity. Oxidative stress may also cause cell apoptosis and release of cellular content into extracellular environment. Altogether, degradation products and cellular content containing oxidized molecules may form a vicious circle, constituted by newly formed ROS and further degradation products. It is now apparent that a very complex intra-cellular regulatory system involving ROS exists within cells.

After its production, NO mediates its biological activities, which can be divided into three categories. Firstly, NO reacts with transition metals (Fe, Cu, Zn), which are abundant in prosthetic groups of enzymes, regulating their activity. NO activates soluble heme-containing cyclic guanylate cyclase (sGC) to produce activated cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). cGMP acts a second messenger as it specifically binds to target proteins which include cGMP-dependent protein kinases (PKG), cAMP-dependent protein kinases phosphodiesterases (PDEs) and cyclic nucleotide-gated channels to elicit a number of biological effects. Simultaneously, NO inhibits Cu-containing cytochrome P-450 enzymes and cytochrome c oxidase in mitochondria, and Fe-containing CAT, resulting in a reduction of the electron transport chain favoring the formation of O2− and H2O2[31]. Secondly, NO can also bind to a reactive cysteine thiol to form S-nitrosothiols, which are very important regulators of physiology and pathology, affecting the activity of enzymes and transcription factors, such as NF-κB, AP-1, p21 kinase, c-Jun N-terminal kinases (JNKs), caspase-3 and caspase-9, through prevalent post-translational protein modification. Under physiologic conditions, protein S-nitrosylation and S-nitrothiosols provide protection preventing further cellular oxidative and nitrosative stress. However, oxidative stress and the resultant dysfunction of NO signaling have been implicated in the pathogenesis of several diseases. Thirdly, NO production in an oxidizing environment, as when O2− is present, leads to the rapid formation of reactive molecules such as peroxynitrite (ONOO−). ONOO− is rapidly decomposed to NO2 and OH− and all together they react with other molecules and radicals. At cellular pH, ONOO− is protonated to form peroxynitrous acid (ONOOH) which is very cytotoxic, causing depletion of − SH groups, oxidation of lipids, DNA strand breakage and deamination of DNA bases. NO can also act in a cGMP-independent manner, by directly modifying proteins or contributing to the oxidation of proteins and lipids, further increasing the complexity and number of potential roles for NO in cellular functions.

ROS are produced at low level in articular chondrocytes, mainly by NADPH oxidase, and they act as integral actors of intracellular signaling mechanisms contributing to the maintenance of cartilage homeostasis as they modulate chondrocyte apoptosis, gene expression, ECM synthesis and breakdown and cytokine production. ROS production and oxidative stress have been found elevated in patients with OA. OA cartilage has significantly more ROS-induced DNA damage than normal cartilage and this damage is mediated by interleukin-1 (IL-1). Evidence for ROS implication in cartilage degradation comes from the presence of lipid peroxidation products, such as oxidized low-density lipoprotein (ox-LDL), nitrite, nitrotyrosine, and nitrated products in the biological fluids and the cartilage of patients with arthritis and in animal models of OA. On the contrary, antioxidant enzymes, such as SOD, CAT, GPX and PON1 are decreased in OA patients, confirming the role of oxidative stress in OA pathogenesis.

References:

• https://www.sciencedirect.com/science/article/pii/S0925443916000041
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