Senescent Mesenchymal Cells Cause Localized Inflammation in Osteoarthritic Cartilage

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.



This an interesting study. But it seems It is a bit more complicated. Some inflammation signalling is needed to maintain the cartilage.(there was a published study a few months ago). Too little and it is not repaired too much and it degenerates. So not all SASP is bad. Some if is necessary . Of course constant/chronic SASP is bad.

As for the Unity Bio trial, it might turn out that knees are not a good candidate for senolytic treatment , at least, not the blunt approach we have now. First, we don't know how effective was the removal of senescent cells in the knee joint. Then we don't know for how long it has to be done. Single dose might not be enough. And it might be too effective preventing the inflammatory signalling needed for the repair.

I highly doubt that a whole body inflammation is the a key contributor, since the inflammation is quite localized and concentrated. Probably if used in the early stages of arthritis first generation senolytics could help but at a later phase there might be other mechanisms at play. From my personal experience fisetin (~2.5g per day over 4 days) helped me with tendinitis and joint pains in my arms. This, of course is hardly a scientific argument.

For now I would lean on the side that Unity Bio didn't have a good senolytic to start with.

All of those studies have to have control groups with ibuprofen/advil and existing senolytics like fisetin and dasatinib. Ideally in slow-release form injected at the site. I suspect they might be quite better than the new candidates, though. Unfortunately, showing that an existing non-patentable (at least not again) compound is not any worse than your candidate small molecule doesn't promise financial profits and there are sever disincentive to be scientifically honest with that.

I would say it would be an easy study to do senolytic injections (D+Q/F) in the knees scheduled for joint replacement operation after a few months. Would be low risk, relatively cheap and with many eligible patients all over the world

Posted by: Cuberat at October 8th, 2021 9:38 AM

@Cube Rat:
'...I would lean on the side that Unity Bio didn't have a good senolytic to start with'
No... why would you? ;p

Unity's flagship senolytic was UBX0101, which was actually a made-up name for the patent-less substance Nutlin 3a, a p53/MDM2 interaction inhibitor.

Posted by: Jones at October 8th, 2021 10:05 AM

With regard to the paper in the topic:
Reading stuff like 'the cell senescence marker p16INK4a' makes me cringe, eversince I read this:
p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a REVERSIBLE response to physiological stimuli
So... how reliable is p16INK4a as a marker for 'real' senescence? How many other cell types have reversible p16INK4a upregulation?

Constitutive p16Ink4a expression, along with senescence-associated β-galactosidase (SAβG), are commonly accepted biomarkers of senescent cells (SCs). Recent reports attributed improvement of the healthspan of aged mice following p16Ink4a-positive cell killing to the eradication of accumulated SCs. However, detection of p16Ink4a/SAβG-positive macrophages in the adipose tissue of old mice and in the peritoneal cavity of young animals following injection of alginate-encapsulated SCs has raised concerns about the exclusivity of these markers for SCs. Here we report that expression of p16Ink4a and SAβG in macrophages is acquired as part of a physiological response to immune stimuli rather than through senescence, consistent with reports that p16Ink4a plays a role in macrophage polarization and response. Unlike SCs, p16Ink4a/SAβG-positive macrophages can be induced in p53-null mice. Macrophages, but not mesenchymal SCs, lose both markers in response to M1- [LPS, IFN-α, Poly(I:C)] and increase their expression in response to M2-inducing stimuli (IL-4, IL-13). Moreover, interferon-inducing agent Poly(I:C) dramatically reduced p16Ink4a expression in vivo in our alginate bead model and in the adipose tissue of aged mice. These observations suggest that the antiaging effects following eradication of p16Ink4a-positive cells may not be solely attributed to SCs but also to non-senescent p16Ink4a/SAβG-positive macrophages.

Posted by: Jones at October 8th, 2021 10:24 AM


What IS a good marker for senescence, and just senescence, then?

Posted by: GREGORY S SCHULTE at October 8th, 2021 11:14 AM

AFAIK there is no universal biomarker for senescence.
A couple are useful for specific cell types, some are not useful in vitro, some not in vivo.

If you're interested,

Biomarkers of Cellular Senescence and Skin Aging

goes into what biomarkers of senescence are useful for which cell type of the human skin. Even with that limited range of cell types, there doesn't seem to be a single universal biomarker.

Posted by: Jones at October 8th, 2021 2:12 PM

@Karl Pfleger
Thank you.

Posted by: Jones at October 10th, 2021 4:26 AM
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