Activation of the noncanonical inflammasome-GSDMD pathway triggers pyroptosis in bone marrow and promotes periosteal bone formation

Evidence indicating that inflammation is commonly associated with ectopic osteogenesis in certain autoimmune and infectious conditions challenges the dogma that inflammatory responses always suppress bone formation. In this study, we find that systemic administration of lipopolysaccharide (LPS) to mice causes not only inflammation in bone marrow, as expected, but also stimulates periosteal bone formation. This response can be reproduced in vitro as bone marrow supernatants from LPS-treated mice induce robust osteogenesis of skeletal stem cells (SSCs) compared to supernatants from PBS-treated counterparts. Periosteal bone accrual is partly dependent on periosteal leptin receptor-positive (LepR) ⁺ SSCs but not bone marrow LepR ⁺ or adiponectin (Adq) ⁺ SSCs and correlates with pyroptosis within bone marrow. Consistent with the dependence of periosteal osteogenesis on pyroptosis, this response is slightly attenuated in Nlrp3 ^-/- or caspase-1 ^-/- mice but significantly inhibited in caspase-11 ^-/- , caspase-1 ^-/- ; caspase-11 ^-/- , or Gsdmd ^-/- mice. Our study reveals a novel role for pyroptosis in which lysed cells release intracellular contents that stimulate osteoprogenitors and promote osteogenic differentiation within the periosteal compartment.