Rapamycin Accelerates TMJ Osteoarthritis in Mice

#1

A loss of primary cilia by a reduction in mTOR signaling correlates with age-related deteriorations in condylar cartilage

Abstract

Age-related deterioration of condylar cartilage is an etiological factor in temporomandibular joint-osteoarthritis (TMJ-OA). … Age-related morphological changes were analyzed using micro-computed tomography and safranin O-stained histological samples of the mandibular condyle of C57BL/6J mice (up to 78 weeks old). … The condylar cartilage demonstrated an age-related reduction in cartilage area, including chondrocyte size, cell density, and cell size distribution. The Golgi size, primary cilia frequency, and mTOR signaling also decreased with age. …

Four-week-old mice receiving an 11-week series of intraperitoneal injections of rapamycin, a potent mTOR signaling inhibitor, were used for the histological evaluation of the condylar cartilage. … Rapamycin injections resulted in both diminished cartilage area and cell size, resembling the phenotypes observed in aged mice. Rapamycin-injected mice also exhibited a smaller Golgi size and lower primary cilia frequency in condylar cartilage.

We demonstrated that a loss of primary cilia due to a decline in mTOR signaling was correlated with age-related deteriorations in condylar cartilage. Our findings provide new insights into the tissue homeostasis of condylar cartilage, contributing to understanding the etiology of age-related TMJ-OA.

Despite several studies showing that rapa reduces the rate of OA in young animals after ACL injury or other acute injury models, this isn’t the first time that rapa has been shown to exacerbate age-related OA. One caveat to this study is that the rapa-treated animals were ridiculously young, so this might have been a developmental effect, although the correlation of declining mTOR activity in the aging TMJ with age-related TMJ OA is suggestive. Fortunately, there was no clear harmful effects in the marmoset study, but this still seems worth monitoring.

5 Likes
#2

Right. In fact I had an immediate record scratch moment when I read “four-week-old mice receiving an 11 weeks series[…]”… whaaa? They are young enough that one wonders if their bones and cartiledge are fully formed, and now they get “intraperitoneal injections” for almost three times as long as they were alive up to this point? And why intraperitoneal injections, rather than pellets shoved down their throats? I think the effect of rapa might be different when it gets absorbed systemically mediated through the digestive system vs delivered directly into a discrete tissue. I do wish that we could have extensive autopsies of both controls and rapa mice from the ITP trial with tissue samples and the full workup, but I find it hard to picture the rapa mice with collapsed jaws starving to death. And if whatever rapa does to their TMJ, it doesn’t prevent them from extending their lifespans vs rapa-free controls, then I’m not going to panic just yet based on this study. YMMV.

I’m not saying it might still not be relevant to humans, but it’s a pretty dramatically different protocol than fully developed middle-to-late age humans taking rapamycin at a different dose and different delivery system.

2 Likes