Activating-mutations in NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) cause neonatal-onset multisystem inflammatory disease. However, the ontogeny of skeletal anomalies in this disorder is poorly understood. Mice globally expressing the D301N mutation in Nlrp3 (D303N in human) model the human phenotype, including systemic inflammation and skeletal deformities. To gain insights into the skeletal manifestations, we generated mice in which the expression of D301N Nlrp3 (Nlrp3 D301N) is restricted to myeloid cells. These mice exhibit systemic inflammation and severe osteopenia (∼ 60% lower bone mass) similar to mice globally expressing the knock-in mutation, consistent with the paradigm of innate immune-driven cryopyrinopathies. Because systemic inflammation may indirectly affect bone homeostasis, we engineered mice in which Nlrp3 D301N is expressed specifically in osteoclasts, the cells that resorb bone. These mice also develop∼ 50% lower bone mass due to increased osteolysis, but there is no systemic inflammation and no change in osteoclast number. Mechanistically, aside from its role in IL-1β maturation, Nlrp3 D301N expression enhances osteoclast bone resorbing ability through reorganization of actin cytoskeleton while promoting the degradation of poly (ADP-ribose) polymerase 1, an inhibitor of osteoclastogenesis. Thus, NLRP3 inflammasome activation is not restricted to the production of proinflammatory mediators but also leads to cytokine-autonomous responses.—Qu, C., Bonar, SL, Hickman-Brecks, CL, Abu-Amer, S., McGeough, MD, Peña, CA, Broderick, L., Yang, C., Grimston, S., K., Kading, J., Abu-Amer, Y., Novack, DV, Hoffman, HM, Civitelli, R., Mbalaviele, G. NLRP3 mediates osteolysis through inflammation-dependent and-independent mechanisms.