Aging vs OA cartilage

Sukhwinderjit Lidder, PhD Departments of Biochemistry Rush University Medical Center Chicago, Illinois Susan Chubinskaya, PhD Professor of Biochemistry, Rheumatology, Orthopedic Surgery Rush University Medical Center Chicago, Illinois OA Not Universal in Older Adults It has long been reported that aging is a physiological event in any organ or tissue, and it is no different in the musculoskeletal system. Although the prevalence of osteoarthritis (OA) increases with age, not all joints in elderly people display characteristics of OA. Furthermore, OA has been observed in younger people as a result of joint injury. In this tutorial we will discuss the age-related changes in healthy joint function, joint tissue structure and composition, and we will compare changes attributed to the normal physiological process of aging vs the changes attributed to the pathological process of OA. Changes in Healthy Joint Function Age-related changes affect normal joint function but do not necessarily directly cause OA. These changes, discussed below, predispose the joint to be more susceptible to OA risk factors, which include abnormal biomechanics, genetics, joint injury, obesity, etc. Sarcopenia is defined as the age-related physiological event that contributes to muscle weakness and loss.1 Twenty-five percent of people aged 70 years and older have sarcopenia, and that percentage increases to 30% to 50% among those aged 80 and older.1 Muscles are known to serve as shock absorbers. An increase in muscle weakness, therefore, can make the joint more susceptible to injury from loading or overloading/overuse, thus increasing the incidence of OA. Some have argued that pain associated with OA can result in decreased use of the muscle, which could also contribute to the development of sarcopenia shown in asymptomatic patients with radiographic OA.2 Decreased proprioception and balance, defined as the decrease in awareness of the position and movement of the limb in space,2 is a change that is seen in healthy aging joints.3 However, similar changes have been identified in OA joints, as well as in the contralateral joints of people with unilateral OA.4 Increased joint laxity, defined as an increased looseness of the joints, is a change that is involved in healthy aging joints and OA joints. Because increased laxity is seen in both the contralateral knee and the OA knee, laxity may be a predisposing but not a determining factor for OA.5 At the joint level, measures such as sarcopenia, decreased proprioception, and joint laxity are not only present in the physiological process of aging, but also in the pathology associated with OA. It is difficult to determine if these changes are the result

of aging or the consequences of early disease processes. However, significant differences do exist at the cellular, tissue, metabolic, and mechanistic levels. Changes in Normal Joint Tissue Structure, Metabolism Several changes are associated with normal joint aging: Brittle cartilage: Aging chondrocytes exhibit decreased anabolic responses to growth factors (for example, insulin-like growth factor-1 (IGF-1) or osteogenic protein-1 (OP1))2,6 and increased catabolic responses causing excessive accumulation of advanced glycation end products (AGEs) that increase collagen cross- linking. This results in changes in cartilage biomechanical properties, making the tissue more brittle and susceptible to fatigue and failure.7 Loss of normal bone structure: Bone modeling, as well as remodeling resulting in either bone formation or resorption, is a process that is usually maintained at a steady state but can change due to the mechanical and cellular environment of the joint. With aging, however, inevitable bone loss occurs, and the microarchitecture of the joint deteriorates, resulting in reduced mechanical strength and fragility fractures. Increased ligament/tendon stiffness: Similar to the brittle cartilage, the main biochemical abnormality in ligament or tendon stiffness is the non-enzymatic glycosilation of collagen with AGE formation, resulting in excessive collagen crosslinking. This in turn alters the biomechanical properties with a decrease in viscoelasticity and tensile strength, and an increase in mechanical stiffness. Meniscal degeneration: Most of the research on aging at the cellular level has focused on cartilage, although Jerosh et al8 have shown with magnetic resonance imaging a correlation of meniscal degeneration advancing with age. Chrondrocyte senescence: As the chondrocytes age they undergo intrinsic or replicative senescence9,10 and extrinsic or stressed-induced senescence.10 In both forms of senescence, the chondrocytes reach a terminal cell cycle arrest, and they have decreased DNA synthesis, telomere shortening, and -galactosidase expression.10 Intrinsic senescence is triggered by telomere shortening that could be p53 dependent. The extrinsic factors include oxidative damage generally seen with the increase of reactive oxygen species, expression of oncogenes and tumor suppressors10 such as p53/p21 and p16/pRb, chronic inflammation,11 and X-ray or ultraviolet radiation.11 Growth factors in aging: Much of the research on the involvement of growth factors in human aging has been limited to bone morphogenetic protein 7 (also known as OP-1) and IGF-1. There is evidence of an age-related decrease in autocrine OP-1 production, due in part to the overmethylation of the OP-1 promoter,12 and in the chondrocyte responses to OP-1 or IGF-1.13 These changes contribute to:

Inhibition of proteoglycan synthesis Decrease in aggrecan core protein Depletion of proteoglycans from the cartilage matrix Down-regulation of IGF-1 and IGF-1 receptors Up-regulation of proinflammatory mediators (cytokines, chemokines, matrix

metalloproteinases, etc).

It is noteworthy that a similar decrease in chondrocyte responses to IGF-1 has been observed with the progression of OA.13 The underlying mechanisms for reduced responses to IGF-1 with aging and OA could be distinct.13 Aging Changes vs OA Changes The table below summarizes differences between aging and OA processes in cartilage: Table: Comparison of aging changes vs. OA changes 9

Epigenetics (changes in histone acetylation, methylation state of the promoters of anabolic and catabolic genes, etc.) has gained more attention over the past few years as the new mechanism contributing to cartilage loss in aging and OA.12, 14,15 Conclusion: In summary, normal aging is a physiological process that could be viewed as the major risk factor for OA. However, there are important differences between these two processes. Age-related changes observed in cells and in the extracellular matrix of joint tissues likely increase the susceptibility to OA when other OA risk factors are present. Clarifying the relationship between aging and OA is crucial to understand the biology of both processes and to determine whether targeting aging changes in the joint could prevent the onset and progression of OA.