Fig. 3.

AMPK and SIRT1 activity in regulation of cartilage homeostasis by increasing chondrocyte stress resistance. Pharmacological activators (e.g., AICAR, A-769662, and metformin), possibly some natural plant products (nutraceuticals), caloric restriction and exercise, activate AMPK in articular chondrocytes. As a result, intracellular NAD⁺ level is increased, leading to activation of SIRT1. Resveratrol, a natural plant product, also activates SIRT1. In turn, SIRT1 activates LKB1, the major upstream kinase of AMPK, through deacetylation of LKB1. Activation of AMPK and SIRT1 coordinates several housekeeping mechanisms to increase chondrocyte stress resistance by increasing mitochondrial biogenesis and function via PGC-1α; inhibiting oxidative stress and via PGC-1α and FOXO3a; attenuating inflammatory responses via inhibition of NF-κB activation, alleviating ER stress via limiting excessive CHOP; and promoting autophagy via suppression of mTOR, ultimately leading to cartilage homeostasis.