Osteoarthritis as an Evolutionary Legacy

"Historically viewed as mainly a “wear and tear” condition, new insights suggest that OA may be part of an evolutionary, age-related biological process rather than mainly driven by mechanical damage."

Osteoarthritis, joint pain, and stiffness are the most common forms of arthritis and increase in incidence as we age. It affects roughly 7% of the world’s population; if you limit that number to the more susceptible, the over-40s, it affects one in every four adults. The NIH defines osteoarthritis as “a degenerative joint disease,” consistent with the everyday wear-and-tear narrative that we wear out those joints. A new study in Osteoarthritis and Cartilage Open challenges that idea. 

Synovial joints are the most common and movable of all our joints and consist of a fibrous outer layer, the joint capsule; a covering of cartilage over the ends of bones to reduce friction and absorb shock; and a synovial membrane on the innermost layer, creating synovial fluid that lubricates and nourishes the joint capsule. Osteoarthritis (OA) is not unique to humans but occurs in many vertebrates with synovial joints. 

Chronic metabolic disease, known to accelerate aging, is associated with a higher incidence of OA. While entangled in the idea that the “excess weight” associated with metabolic disease exacerbates wear and tear, the finding that OA progresses in all species at a rate that aligns with life expectancy rather than simply use suggests that biological aging plays a significant role. That hypothesis gains further credibility from studies in mice, where accelerated aging is often accompanied by OA-like changes. In short, for OA wear and tear causality, there is a disconnect between our chronological and biological ages. 

When Good Cartilage Breaks Bad

Our skeleton grows by endochondral ossification, a choreographed conversion of pliable cartilage into bone. At the center of this process are chondrocytes, living within cartilage’s matrix, that enlarge (becoming “hypertrophic”), summoning blood vessels, dissolving their matrix, and finally calcifying, providing a scaffold for incoming bone cells. Once our growth plates close, we have always thought this dance ends. 

Healthy cartilage requires stress, in the form of weight bearing, to thrive. Mechanical compression of our joints, from our moment-to-moment movements, activates transforming growth factor-β (TGF-β), which inhibits chondrocytes from becoming hypertrophic and laying down new bone. TGF-β is a signal to chill out. When we are immobile and our joints “unloaded,” there is a rapid loss of this protective TGF-β signaling, making the articular cartilage more susceptible to chondrocyte hypertrophy and processes resembling endochondral ossification. For example,  individuals with spinal cord injuries lose knee cartilage quickly. 

Aging adds a critical twist: elderly cartilage becomes deaf to the mechanical whisper—less TGF-β is released, and the signal weakens. The same daily steps that once protected now barely hold the line, priming the tissue for a “mistimed re-awakening” of bone formation within our joints. 

As with all aspects of our physiology, multiple factors contribute to symptomatic OA. Genetics plays a role, as many genes associated with the risk of OA are involved in bone formation. In addition to the metabolic consequences of what we eat, there are lifestyle choices about how we “load” our joints, including repetitive microtraumas, e.g., tennis and golfer’s elbow, stress fractures of the tibia from running. More significant trauma, like a twisted knee, pours gasoline on the smoldering process as our body rushes to repair with a tool no longer suited for the times.

This mismatch in timing and place has an evolutionary name: antagonistic pleiotropy. Genes that are beneficial early in life can be maintained by natural selection because their adverse effects are only experienced after our reproductive years.  

"Comprehending OA within this evolutionary and biological frame provides a solid alternative to the theory of “wear and tear,” offering insights into further understanding, prevention and disease management."

Re-awakening this misplaced endochondral ossification does not automatically cause painful osteoarthritis. Many people show substantial radiographic damage yet feel little or no discomfort because symptom severity comes with time and is shaped by genetics, lifestyle, past injuries, and, dare I say, chance. 

Treatment follows understanding

Our therapeutic options in OA are limited primarily to treating symptoms rather than underlying “causes.” Symptomatic treatment encompasses a range of pharmaceuticals designed to provide pain relief, reduce downstream inflammation, and promote lubrication. Physical therapy can help strengthen or stabilize joints to minimize the impact of unloading and alleviate the pain associated with the now-permanent anatomical changes. Surgery can replace the joint with an “almost as good” prosthesis. 

However, a shift in how we understand OA, recognizing that it is more than wear and tear and that it has roots in our biological rather than chronological age, suggests that earlier intervention before the onset of symptoms would be beneficial. We can do little to alter our genetics, but we can change our lifestyle in terms of what we eat and how and when we move. For those who suffer from OA, we can also look for pharmaceuticals directed at the signaling that renews the onset of mismatched, mistimed endochondral ossification. 

Source: Osteoarthritis As An Evolutionary Legacy: Biological Ageing And Chondrocyte Hypertrophy Osteoarthritis and Cartilage Open DOI: 10.1016/j.ocarto.2025.100624