All age-related diseases are complex enough to have many facets through which they can be viewed, each facet being just one stage or one contributing cause, or one viewpoint on the disease process as a whole. An entire ecosystem of theory and potential therapies can be built within one facet without ever having to consider other mechanisms. Since specialization is necessary to make progress in the life sciences, this is usually how matters in fact progress: for every disease, there are many research groups with very different points of focus. The big picture must be assembled from a synthesis of all of their views.

Looking at the degenerative joint condition of osteoarthritis, for example, we might firstly consider it as an inflammatory condition. This view focuses on age-related immune dysfunction and tissue conditions that promote greater local inflammation. Therapies attempt to suppress the inflammatory response. A more recent alternative viewpoint is to see osteoarthritis as a cellular issue - one of the more direct consequences of growing numbers of senescent cells accumulating in tissues. Here, research centers on understanding how the signals generated by these cells cause such pervasive damage to joint tissue, and how to safely remove the unwanted senescent cells.

For a third facet, look no further than the papers presented below, in which osteoarthritis is considered a systemic condition in which cartilage tissue ceases to correctly regulate and maintain itself due to changes in specific signals or protein levels. Here, researchers look for proximate causes in the proteins and signals that alter with age, and seek treatments that can force restoration of a more youthful configuration. In this particular case, the researchers involved have focused on adenosine and related proteins that interact with adenosine in cartilage cells. They present evidence for the lack of adenosine to be important in the decline of aged cartilage, including a demonstration to show that delivery of additional adenosine in order to delay the onset of the symptoms of osteoarthritis in laboratory mice.

Rodents with Trouble Walking Reveal Potential Treatment Approach for Most Common Joint Disease

Researchers have provided evidence that adenosine, a biochemical at the heart of human cellular function, plays another crucial role - keeping on hand a steady number of healthy chondrocytes, the cells that make and sustain cartilage. Important to the study's implications, adenosine is derived from adenosine triphosphate (ATP), the molecule that stores the energy needed by the body's cells until they break it up to use it. Scientists have known that both inflammation and aging lead to diminished ATP production (and so lower adenosine levels) in chondrocytes. Until now, they had not linked diminished adenosine levels to osteoarthritis, the commonplace, "wear-and-tear" form of arthritis. The study found that maintaining high levels of adenosine in rats with damage to the anterior cruciate ligament (ACL), which is known to lead to osteoarthritis in humans, prevented the rats from developing the disease. If the finding proves to be true in humans, adenosine replacement therapy could potentially delay the onset of osteoarthritis and the need for joint replacements. The findings suggest that reductions in the number of cartilage-producing cells, and greater risk for osteoarthritis, may be driven not just by lower adenosine levels but also by lower levels of the protein on the surface of chondrocytes designed to receive and pass on adenosine's signal. Adenosine helps to sustain such cells by fitting into a protein called the A2A adenosine receptor on their surfaces, like a key into a lock. Researchers observed that mice lacking the A2A adenosine receptor did not walk as easily or as well as mice with the receptor. Radiologic examination of the knees of mice without the receptor confirmed that they had osteoarthritis. The team also found that levels of adenosine A2A receptors went up on rat chondrocytes when osteoarthritis was present, in what the researchers say was a "failed attempt" to compensate for the loss of adenosine from the energy-processing (metabolic) changes underlying the inflammation. Additional tests in tissue samples from osteoarthritic patients who had joint replacements found similarly increased levels of adenosine A2A receptors on chondrocytes. When researchers treated mouse chondrocytes with a molecule called IL-1beta, which contributes to the development of osteoarthritis, they found that 39 percent less ATP was produced by the inflamed chondrocytes. They also found 80 percent less expression of ANKH, a molecule that exports ATP, in the IL-1beta-treated cells. Finally, they found that lacking the enzyme involved in turning ATP into adenosine caused diminished adenosine levels, which led to osteoarthritis in mice. The lack of the enzyme in humans is also known to lead to the disease. When the team administered adenosine packaged in lipid bubbles into rats' ACL injuries, researchers found that the excess adenosine, as mediated by the adenosine A2A receptor, prevented the development of osteoarthritis in the animals.

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression