The integrin family of cell adhesion receptors plays a major role in mediating interactions between cells and the extracellular matrix. Normal adult articular chondrocytes express α1β1, α3β1, α5β1, ...α10β1, αVβ1, αVβ3, and αVβ5 integrins, while chondrocytes from osteoarthritic tissue also express α2β1, α4β1, α6β1. These integrins bind a host of cartilage extracellular matrix (ECM) proteins, most notably fibronectin and collagen types II and VI, which provide signals that regulate cell proliferation, survival, differentiation, and matrix remodeling. By initiating signals in response to mechanical forces, chondrocyte integrins also serve as mechanotransducers. When the cartilage matrix is damaged in osteoarthritis, fragments of fibronectin are generated that signal through the α5β1 integrin to activate a pro-inflammatory and pro-catabolic response which, if left unchecked, could contribute to progressive matrix degradation. The cell signaling pathways activated in response to excessive mechanical signals and to fibronectin fragments are being unraveled and may represent useful therapeutic targets for slowing or stopping progressive matrix destruction in arthritis.
The development of osteoarthritis (OA) correlates with a rise in the number of senescent cells in joint tissues, and the senescence-associated secretory phenotype (SASP) has been implicated in ...cartilage degradation and OA. Age-related mitochondrial dysfunction and associated oxidative stress might induce senescence in joint tissue cells. However, senescence is not the only driver of OA, and the mechanisms by which senescent cells contribute to disease progression are not fully understood. Furthermore, it remains uncertain which joint cells and SASP-factors contribute to the OA phenotype. Research in the field has looked at developing therapeutics (namely senolytics and senomorphics) that eliminate or alter senescent cells to stop disease progression and pathogenesis. A better understanding of how senescence contributes to joint dysfunction may enhance the effectiveness of these approaches and provide relief for patients with OA.
Osteoarthritis (OA) is the most common cause of chronic disability in older adults. Although classically considered a "wear and tear" degenerative condition of articular joints, recent studies have ...demonstrated an inflammatory component to OA that includes increased activity of several cytokines and chemokines in joint tissues that drive production of matrix-degrading enzymes. Rather than directly causing OA, aging changes in the musculoskeletal system contribute to the development of OA by making the joint more susceptible to the effects of other OA risk factors that include abnormal biomechanics, joint injury, genetics, and obesity. Age-related sarcopenia and increased bone turnover may also contribute to the development of OA. Understanding the basic mechanisms by which aging affects joint tissues should provide new targets for slowing or preventing the development of OA.
Osteoarthritis (OA) is the most common joint disease, affecting an estimated more than 240 million people worldwide, including an estimated more than 32 million in the US. Osteoarthritis is the most ...frequent reason for activity limitation in adults. This Review focuses on hip and knee OA.
Osteoarthritis can involve almost any joint but typically affects the hands, knees, hips, and feet. It is characterized by pathologic changes in cartilage, bone, synovium, ligament, muscle, and periarticular fat, leading to joint dysfunction, pain, stiffness, functional limitation, and loss of valued activities, such as walking for exercise and dancing. Risk factors include age (33% of individuals older than 75 years have symptomatic and radiographic knee OA), female sex, obesity, genetics, and major joint injury. Persons with OA have more comorbidities and are more sedentary than those without OA. The reduced physical activity leads to a 20% higher age-adjusted mortality. Several physical examination findings are useful diagnostically, including bony enlargement in knee OA and pain elicited with internal hip rotation in hip OA. Radiographic indicators include marginal osteophytes and joint space narrowing. The cornerstones of OA management include exercises, weight loss if appropriate, and education-complemented by topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs) in those without contraindications. Intra-articular steroid injections provide short-term pain relief and duloxetine has demonstrated efficacy. Opiates should be avoided. Clinical trials have shown promising results for compounds that arrest structural progression (eg, cathepsin K inhibitors, Wnt inhibitors, anabolic growth factors) or reduce OA pain (eg, nerve growth factor inhibitors). Persons with advanced symptoms and structural damage are candidates for total joint replacement. Racial and ethnic disparities persist in the use and outcomes of joint replacement.
Hip and knee OA are highly prevalent and disabling. Education, exercise and weight loss are cornerstones of management, complemented by NSAIDs (for patients who are candidates), corticosteroid injections, and several adjunctive medications. For persons with advanced symptoms and structural damage, total joint replacement effectively relieves pain.
Abstract This review is focused on aging-related changes in cells and extracellular matrix of the articular cartilage. Major extracellular matrix changes are a reduced thickness of cartilage, ...proteolysis, advanced glycation and calcification. The cellular changes include reduced cell density, cellular senescence with abnormal secretory profiles, and impaired cellular defense mechanisms and anabolic responses. The extracellular and cellular changes compound each other, leading to biomechanical dysfunction and tissue destruction. The consequences of aging-related changes for joint homeostasis and risk for osteoarthritis are discussed. This article is part of a Special Issue entitled “ Osteoarthritis ”.
Aging is a primary risk factor for the development of osteoarthritis and the understanding of how aging processes contribute to the development of osteoarthritis is an important area of active ...research. The most recent literature in this area was reviewed in order to update investigators on the status of the field.
The field is beginning to move beyond a cartilage focus to include other joint tissues relevant to osteoarthritis such as ligaments, meniscus, and bone. Synovitis also appears to play a role in osteoarthritis but has not been a focus of aging studies. Studies in small animals, including mice and rats, demonstrate age-related changes that can contribute to osteoarthritis and show that animal age is a key factor to be considered in interpreting the results of studies using surgically induced models of osteoarthritis. There is accumulating evidence that cellular processes such as damage-induced cell senescence contribute to osteoarthritis and a growing body of literature on the role of epigenetic regulation of gene expression in aging and osteoarthritis.
Not all osteoarthritis is due to aging processes in joint tissues, but the age-related changes being discovered certainly could play a major contributing role.
Abstract
OA is a multifaceted and heterogeneous syndrome that may be amenable to tailored treatment. There has been an increasing focus within the OA research community on the identification of ...meaningful OA phenotypes with potential implications for prognosis and treatment. Experimental and clinical data combined with sophisticated statistical approaches have been used to characterize and define phenotypes from the symptomatic and structural perspectives. An improved understanding of the existing phenotypes based on underlying disease mechanisms may shed light on the distinct entities that make up the disease. This narrative review provides an updated summary of the most recent advances in this field as well as limitations from previous approaches that can be addressed in future studies.
Aging and osteoarthritis Loeser, Richard F
Current opinion in rheumatology
23, Številka:
5
Journal Article
Odprti dostop
Osteoarthritis is strongly linked to aging but the mechanisms for this link are incompletely understood. The recent literature was reviewed to find studies providing new insights into the connection ...between aging and osteoarthritis.
Basic aging studies in nonarticular cells suggest that a cell stress or cell damage response contributes to chronic inflammation that promotes age-related diseases. This cellular response results in the senescence-associated secretory phenotype which has many of the characteristics of an osteoarthritic chondrocyte in terms of the cytokines, chemokines, and proteases produced. Oxidative stress can promote cell senescence and studies have shown a role for oxidative stress in altering cell signaling pathways in chondrocytes that can disrupt the response to growth factors. Mitochondria are an important source of reactive oxygen species and studies continue to support a role for the mitochondria in osteoarthritis, including work suggesting changes in energy production. Cell death occurs in osteoarthritic cartilage and recent studies suggest autophagy may play a role in determining if a cell lives or dies when stressed.
Continued progress is being made on characterizing aging-related changes in cartilage. Additional studies are needed that focus on the tissues outside of the articular cartilage that play a role in osteoarthritis. Because osteoarthritis occurs in older adults who also have age-related changes in muscle, bone, fat, and the nervous system, it is likely that a more general and systemic approach will be needed to better understand the link between aging and osteoarthritis.
Chondrocytes are responsible for the maintenance of the articular cartilage. A loss of homeostasis in cartilage contributes to the development of osteoarthritis (OA) when the synthetic capacity of ...chondrocytes is overwhelmed by processes that promote matrix degradation. There is evidence for an age-related imbalance in reactive oxygen species (ROS) production relative to the anti-oxidant capacity of chondrocytes that plays a role in cartilage degradation as well as chondrocyte cell death. The ROS produced by chondrocytes that have received the most attention include superoxide, hydrogen peroxide, the reactive nitrogen species nitric oxide, and the nitric oxide derived product peroxynitrite. Excess levels of these ROS not only cause oxidative-damage but, perhaps more importantly, cause a disruption in cell signaling pathways that are redox-regulated, including Akt and MAP kinase signaling. Age-related mitochondrial dysfunction and reduced activity of the mitochondrial superoxide dismutase (SOD2) are associated with an increase in mitochondrial-derived ROS and are in part responsible for the increase in chondrocyte ROS with age. Peroxiredoxins (Prxs) are a key family of peroxidases responsible for removal of H2O2, as well as for regulating redox-signaling events. Prxs are inactivated by hyperoxidation. An age-related increase in chondrocyte Prx hyperoxidation and an increase in OA cartilage has been noted. The finding in mice that deletion of SOD2 or the anti-oxidant gene transcriptional regulator nuclear factor-erythroid 2- related factor (Nrf2) result in more severe OA, while overexpression or treatment with mitochondrial targeted anti-oxidants reduces OA, further support a role for excessive ROS in the pathogenesis of OA. Therefore, new therapeutic strategies targeting specific anti-oxidant systems including mitochondrial ROS may be of value in reducing the progression of age-related OA.
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•An age-related increase in chondrocyte reactive oxygen species (ROS) levels exists.•Mitochondrial dysfunction contributes to oxidative stress in osteoarthritis.•Excessive ROS levels alter signaling to promote cartilage matrix destruction.
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