Ablation of hypothalamic Cnr1 leads to reduced meniscal mineral volume and articular cartilage damage in aging male mice.

OBJECTIVE

Aging is associated with reduced central nervous system endocannabinoid tone. Here we ‎sought to decipher the involvement of hypothalamic cannabinoid receptor type-1 (Cnr1) in ‎driving peripheral tissue aging, with a particular focus on bone and joint structural changes.

METHODS

To this end, we generated mice with hypothalamus-specific ablation of Cnr1 (i.e., CB1hypoKO), or with hypothalamus-specific rescue of the receptor (CB1STOPhypoRS) using stereotaxic viral injections into the mediobasal hypothalamus at 2-3-‎months of age in Cnr1fl/fl or CB1STOP mice. Animals were aged to 18 or 19 months and assessed for body weight, ‎temperature, frailty and circulating hormones. After sacrifice, we examined structural and histological features of hypothalamic tissue, skin, ‎testis, joint, and bone as well as circulating hormone levels.

RESULTS

CB1hypoKO exhibited reduced frailty index vs WT at 17 months of age, with unchanged body weight, temperature and survival. Interestingly, CB1hypoKO mice displayed a reduction in the lateral meniscal ‎mineral volume of the tibiofemoral joint, which was associated with less blood vessels and articular cartilage damage. Immunofluorescence analysis revealed that CB1hypoKO mice displayed enriched tyrosine hydroxylase (TH) intensity surrounding blood vessels, yet meniscal tissue showed reduced TH positive cells and ATF4 nuclear co-appearence in CB1hypoKO mice vs WT. Finally, CB1hypoKO mice displayed signficantly lower circulating levels of corticosterone.

CONCLUSIONS

These results suggest that a lack of hypothalamic CB1 tone reduced circulating levesl of corticosterone, while increasing local meniscal sympathetic tone, which is associated with impaired ATF4 nuclear localization and meniscal mineralization. These events subsequently hinder OA development with age.