Given the failure of a locally injected senolytic drug to make a meaningful impact in osteoarthritis, the present consensus at the senolytics end of the longevity industry appears to be that systemic inflammatory signalling from senescent cells elsewhere in the body outweighs the contribution of local senescent cells in osteoarthritic joints. But perhaps the senolytic drug used in the failed trial was not a good candidate for humans; it remains to be seen as to whether better outcomes can be produced by systemic senolytic approaches in clinical trials for osteoarthritis. Meanwhile, researchers here suggest that there is in fact a meaningful contribution to harmful inflammation arising from senescent cells in osteoarthritic cartilage, and propose that the nature of the senescent cell population may explain some of the apparently contradictory past results.
Although osteoathritis (OA) was considered as a non-inflammatory disease, an ever-increasing body of evidence suggests that chronic degeneration of the joint is associated with persistent long-term low-grade inflammation in the joint. The source of inflammation in OA is unknown, although it has been shown to associate with high-fat diet, mechanical injury, and aging. We have shown here that one of the sources of joint inflammation is mesenchymal stromal cells (OA-MSC) within cartilage itself. OA-MSC synthesizes pro-inflammatory cytokines and chemokines that have been implicated in OA pathogenesis. We demonstrated that the induction of such pro-inflammatory molecules occurs at both mRNA and protein levels. We have also shown that the induction of inflammation in OA cartilage occurs during the transition from normal cartilage stromal cell (NCSC) in the young to the OA-MSC in the old during aging.
In recent years, cell senescence has been shown to be closely associated with OA pathogenesis. Injection of senescent cells into the joint space led to joint degeneration. Conversely, local clearance of p16INK4a-positive senescent cells from the joint attenuated injury and aging induced OA. Although the role of senescent cells in causing joint degeneration has been established, the molecular mechanism by which a chondrocyte reaches senescence has not been well understood. The expression levels of the cell senescence marker p16INK4a and senescence-associated secretory phenotype (SASP) were elevated in the serial passages of human chondrocyte culture in vitro and in aged human and mouse cartilage in vivo. However, inactivation of p16INK4a in chondrocytes of adult mice failed to attenuate joint degeneration during aging or injury. This observation raised an important question whether senescent chondrocytes were involved in cartilage degeneration.
We have shown here for the first time that OA-MSC, but not OA chondrocytes (OAC), has elevated levels of p16INK4a and SASP. Therefore, OA-MSC, but not OAC, are the senescent cells that become a source of inflammation in the joint. Our study also provided a plausible molecular explanation to the observation that joint degeneration was not affected when the p16INK4a gene was deleted in chondrocytes. Since p16 is expressed at very low levels in the OAC, targeting OAC for p16 knockout might not affect the real source of cell senescence in OA cartilage. Our data predict that joint degeneration would be attenuated if p16 were knocked out in OA-MSC, since it would abolish the source of SASP in OA cartilage. Although this prediction remains to be tested, OA-MSC should be considered as potential target cells of senolytics and anti-inflammation therapy for OA intervention in future studies.