Non-pyroptotic caspase-11 activity regulates osteoclastogenesis and pathological bone loss.

Osteoclasts are essential for bone remodeling; however, their hyperactivity leads to pathological bone loss. While inflammasome-activated caspases are known to influence osteoclastogenesis, the role of caspase-11, beyond its conventional function in pyroptosis, remains unclear. Here, we identified caspase-11 as a pivotal regulator of RANKL-induced osteoclast differentiation. Caspase-11 expression and activity were elevated in bone tissues exhibiting excessive resorption and in RANKL-stimulated bone marrow-derived macrophages. Unlike inflammasome activation, RANKL-induced caspase-11 did not trigger typical inflammasome-associated inflammatory responses. Caspase-11 knockout mice displayed increased bone mass and resistance to RANKL-induced bone resorption; in parallel, genetic or pharmacological inhibition of caspase-11 impaired osteoclast differentiation in vitro. Notably, mechanistic studies revealed that RANKL-activated caspase-11 translocates to the nucleus, where it cleaves and inactivates poly(ADP-ribose) polymerase 1 (PARP1), a transcriptional repressor of osteoclastogenesis. In addition, using the caspase-11 inhibitor, VX-765, substantially reduced ovariectomy-induced bone loss. These findings collectively reveal a novel, non-inflammatory function of caspase-11 in osteoclastogenesis, positioning it as a promising therapeutic target for osteolytic diseases.