Life Extension - Age related disease

Degenerative Joint Disiease - updated: 23 February 2009

Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis

Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1181-6

Taniguchi N, Caramés B, Ronfani L, Ulmer U, Komiya S, Bianchi ME, Lotz M.

Osteoarthritis (OA) is the most common joint disease and typically begins with an aging-related disruption of the articular cartilage surface. Mechanisms leading to the aging-related cartilage surface degeneration remain to be determined. Here, we demonstrate that nonhistone chromatin protein high-mobility group box (HMGB) protein 2 is uniquely expressed in the superficial zone (SZ) of human articular cartilage. In human and murine cartilage, there is an aging-related loss of HMGB2 expression, ultimately leading to its complete absence. Mice genetically deficient in HMGB2 (Hmgb2(-/-)) show earlier onset of and more severe OA. This is associated with a profound reduction in cartilage cellularity attributable to increased cell death. These cellular changes precede glycosaminoglycan depletion and progressive cartilage erosions. Chondrocytes from Hmgb2(-/-) mice are more susceptible to apoptosis induction in vitro. In conclusion, HMGB2 is a transcriptional regulator specifically expressed in the SZ of human articular cartilage and supports chondrocyte survival. Aging is associated with a loss of HMGB2 expression and reduced cellularity, and this contributes to the development of OA.

Publication Types:

• Study

Aging, articular cartilage chondrocyte senescence and osteoarthritis

Biogerontology. 2002;3(5):257-64

Martin JA, Buckwalter JA.

The incidence of osteoarthritis (OA), the disease characterized by joint pain and loss of joint form and function due to articular cartilage degeneration, is directly correlated with age. The strong association between age and increasing incidence of osteoarthritis (OA) marks OA as an age related disease. Yet, like many other age related diseases, OA is not an inevitable consequence of aging; instead, aging increases the risk of OA. Articular cartilage aging changes that may lead to articular cartilage degeneration include fraying and softening of the articular surface, decreased size and aggregation of proteoglycan aggrecans and loss of matrix tensile strength and stiffness. These changes most likely are the result of an age related decrease in the ability of chondrocytes to maintain and repair the tissue manifested by decreased mitotic and synthetic activity, decreased responsiveness to anabolic growth factors and synthesis of smaller less uniform aggrecans and less functional link proteins. Our recent work suggests that progressive chondrocyte senescence marked by expression of the senescence associated enzyme beta-galactosidase, erosion of chondrocyte telomere length and mitochondrial degeneration due to oxidative damage causes the age related loss of chondrocyte function. New efforts to prevent the development and progression of OA might include strategies that slow the progression of chondrocyte senescence or replace senescent cells.

Publication Types:

• Review

Osteoarthritis: aging of matrix and cells--going for a remedy

Curr Drug Targets. 2007 Feb;8(2):325-31

Aigner T, Haag J, Martin J, Buckwalter J.

It has been known for a very long time that aging is the most prominent risk factor for the initiation and progression of osteoarthritis. This might be related to continuous mechanical wear and tear and/or result from time/age-related modifications of cartilage matrix components. Also a mere loss of viable cells over time, due to apoptosis or any other mechanism, might contribute. More recent evidence, however, supports that stressful conditions for the cells might promote chondrocyte senescence and might be in particular important for the progression of the osteoarthritic disease process. One of the most important implications of this hypothesis is that it points to issues of cellular degeneration as the basis for understanding of the initiation and the progression of osteoarthritis. Equally important, it emphasizes that whatever treatment we envisage for osteoarthritis, we must take into account that we are dealing with aged/(pre)senescent cells which no longer have the abilities of their juvenile counterparts to respond to the many mechanical, inflammatory, and traumatic assaults to the tissue. Thirdly, this directs treatment options to deal with the senescence of cells, which are only conceptually available today. Clearly, if accumulation of wear and tear over time is the major scenario of osteoarthritis, any therapy will largely be hopeless as moving and loading the joints is unavoidable as implication of their use. However, this review intends to open up the idea that age-related changes are less a fate, but rather a challenge for therapeutic intervention which can be taken.

Publication Types:

• Review

Aging theories of primary osteoarthritis: from epidemiology to molecular biology

Rejuvenation Res. 2004 Summer;7(2):134-45

Aigner T, Rose J, Martin J, Buckwalter J.

Osteoarthritis is the most common disabling condition of humans in the western world. It has been known for a very long time that aging is the most prominent risk factor for the initiation and progression of the disease, but the explanations for this phenomenon have changed over time. The most longstanding theory is that osteoarthritis develops because of continuous mechanical wear and tear. However, osteoarthritis can also be the result of time/age-related modifications to cartilage matrix components. One of the simplest biological explanations for the initiation and progression of osteoarthritic cartilage degeneration is a mere loss of viable cells, due to apoptosis or other mechanisms. Overall, the most likely scenario is that the cells and the matrix of articular cartilage get older over time, and eventually the tissue enters a senescence-like state that makes it more prone to enter the osteoarthritic degeneration pathway. Thus, patients with osteoarthritis might progress more quickly to the senescence phenotype compared to others. Moreover, stressful conditions associated with the osteoarthritic disease process might further promote chondrocyte senescence. Primary osteoarthritis in this model would be a "premature" degeneration of the joint due to a premature chondrocyte senescence. By analogy to neurodegenerative disorders, one could refer to osteoarthritis as the "M. Alzheimer" of articular cartilage. One of the most important implications of this hypothesis is that it points to issues of cellular degeneration as the basis for understanding the initiation and progression of osteoarthritis. Equally important, it emphasizes that whatever treatment we envisage for osteoarthritis, we must take into account that we are dealing with aged/(pre)senescent cells that no longer have the ability of their juvenile counterparts to counteract the many mechanical, inflammatory, and/or other assaults to the tissue.

Publication Types:

• Review

Publication Types:

• Review