Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.
All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."
"So mechanical stress is a cytokine," he stated.
Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."
Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.
Courtesy Dr. Francis Berenbaum
Dr. Francis Berenbaum
To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."
Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."
"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.
Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.
He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.
In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.
Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.
Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."
An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."
He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."
The congress was sponsored by Osteoarthritis Research Society International.