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.
Summary Objective Age-related changes in multiple components of the musculoskeletal system may contribute to the well established link between aging and osteoarthritis (OA). This review focused on ...potential mechanisms by which age-related changes in the articular cartilage could contribute to the development of OA. Methods The peer-reviewed literature published prior to February 2009 in the PubMed database was searched using pre-defined search criteria. Articles, selected for their relevance to aging and articular chondrocytes or cartilage, were summarized. Results Articular chondrocytes exhibit an age-related decline in proliferative and synthetic capacity while maintaining the ability to produce pro-inflammatory mediators and matrix degrading enzymes. These findings are characteristic of the senescent secretory phenotype and are most likely a consequence of extrinsic stress-induced senescence driven by oxidative stress rather than intrinsic replicative senescence. Extracellular matrix changes with aging also contribute to the propensity to develop OA and include the accumulation of proteins modified by non-enzymatic glycation. Conclusion The effects of aging on chondrocytes and their matrix result in a tissue that is less able to maintain homeostasis when stressed, resulting in breakdown and loss of the articular cartilage, a hallmark of OA. A better understanding of the basic mechanisms underlying senescence and how the process may be modified could provide novel ways to slow the development of OA.
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.
Summary It is well accepted that aging is an important contributing factor to the development of osteoarthritis (OA). The mechanisms responsible appear to be multifactorial and may include an ...age-related pro-inflammatory state that has been termed “inflamm-aging.” Age-related inflammation can be both systemic and local. Systemic inflammation can be promoted by aging changes in adipose tissue that result in increased production of cytokines such as interleukin (IL)-6 and tumor necrosis factor-α (TNFα). Numerous studies have shown an age-related increase in blood levels of IL-6 that has been associated with decreased physical function and frailty. Importantly, higher levels of IL-6 have been associated with an increased risk of knee OA progression. However, knockout of IL-6 in male mice resulted in worse age-related OA rather than less OA. Joint tissue cells, including chondrocytes and meniscal cells, as well as the neighboring infrapatellar fat in the knee joint, can be a local source of inflammatory mediators that increase with age and contribute to OA. An increased production of pro-inflammatory mediators that include cytokines and chemokines, as well as matrix-degrading enzymes important in joint tissue destruction, can be the result of cell senescence and the development of the senescence-associated secretory phenotype (SASP). Further studies are needed to better understand the basis for inflamm-aging and its role in OA with the hope that this work will lead to new interventions targeting inflammation to reduce not only joint tissue destruction but also pain and disability in older adults with OA.
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.
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.
Summary The purpose of this review was to present highlights from the published literature on the topic of the biology of osteoarthritis (OA). A PubMed search was conducted in order to locate ...original research manuscripts published since the last OARSI meeting in 2012. From review of the published literature, common themes emerged as active areas of research over the past year including studies in the areas of epigenetics, Wnt signaling, the role of inflammatory pathways in OA, lubricin, fibroblast growth factor signaling, and studies on OA biology in bone. Key findings in these areas were summarized and implications for future therapies were discussed.
Why is osteoarthritis an age-related disease? Shane Anderson, A., MD, Fellow in Rheumatology; Loeser, Richard F., MD, Professor of Internal Medicine and Chief
Best practice & research. Clinical rheumatology,
02/2010, Letnik:
24, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Although older age is the greatest risk factor for osteoarthritis (OA), OA is not an inevitable consequence of growing old. Radiographic changes of OA, particularly osteophytes, are common in the ...aged population, but symptoms of joint pain may be independent of radiographic severity in many older adults. Ageing changes in the musculoskeletal system increase the propensity to OA but the joints affected and the severity of disease are most closely related to other OA risk factors such as joint injury, obesity, genetics and anatomical factors that affect joint mechanics. The ageing changes in joint tissues that contribute to the development of OA include cell senescence that results in development of the senescent secretory phenotype and ageing changes in the matrix including formation of advanced glycation end-products that affect the mechanical properties of joint tissues. An improved mechanistic understanding of joint ageing will likely reveal new therapeutic targets to slow or halt disease progression. The ability to slow progression of OA in older adults will have enormous public health implications given the ageing of our population and the increase in other OA risk factors such as obesity.
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