Fig. 7

Acetyl-CoA generation is central to CTSK production. Rheb1 localizes to mitochondria and regulates mitochondrial respiration in multinucleated osteoclasts. When osteoclasts attach to substrates rich in type I or type II collagen, mitochondrial respiration is enhanced, promoting CTSK protein expression. Rheb1 deletion impairs mitochondrial respiration in osteoclasts, reduces acetyl-CoA production, and specifically inhibits CTSK expression and the collagen degradation ability of osteoclasts. Under physiological conditions, mitochondria-derived acetyl-CoA is necessary for osteoclasts to produce CTSK, though other sources of acetyl-CoA can also assist in CTSK production. The availability of acetyl-CoA determines the level of CTSK production in osteoclasts, thereby affecting bone and cartilage matrix homeostasis. CTSK cathepsin K, OC osteoclast, TCA tricarboxylic acid cycle