NLRP3 is involved in long bone edification and the maturation of osteogenic cells

Abstract

Overexpression of the nucleotide-binding leucine-rich repeat protein 3 (NLRP3) inflammasome in chronic auto-immune diseases leads to skeletal anomalies, with severe osteopenia due to the activation of osteoclasts. Reproducing this phenotype in Nlrp3 knock-in mice has provided insights into the role of NLRP3 in bone metabolism. We studied the role of NLRP3 in physiological bone development using a complete Nlrp3 knockout mouse model. We found impaired skeletal development in Nlrp3 −/− mice, resulting in a shorter stature than that of Nlrp3 +/+ mice. These growth defects were associated with altered femur bone growth, characterized by a deficient growth plate and an osteopenic profile of the trabeculae. No differences in osteoclast recruitment or activity were observed. Instead, Nlrp3 −/− femurs showed a less mineralized matrix in the trabeculae than those of Nlrp3 +/+ mice, as well as less bone sialoprotein (BSP) expressing hypertrophic chondrocytes. In vitro, primary osteoblasts lacking NLRP3 expression showed defective mineralization, together with the downregulation of BSP expression. Finally, follow-up by micro-CT highlighted the role of NLPR3 in bone growth, occurring early in living mice, as the osteopenic phenotype diminishes over time. Overall, our data suggest that NLRP3 is involved in bone edification via the regulation of hypertrophic chondrocyte maturation and osteoblast activity. Furthermore, the defect appeared to be transitory, as the skeleton recovered with aging.

NLRP3 Is Involved in Neutrophil Mobilization in Experimental Periodontitis

“…We quantified the number of cells expressing NLRP3 in connective tissue of WT animals. As expected, in NLRP3 KO mice, no expression of NLRP3 was detected (not shown), confirming the specificity of NLRP3 antibody, and as previously described ( 18 ). In WT mice, while the non-treated connective tissue virtually did not show any detectable NLRP3 expression, we could evidence a strong NLRP3 expression on the right side, treated with ligature alone or with P. gingivalis ( Figure 5A + enlargement).…”

“…The aim of the current study is to better understand NLRP3 implication during the onset of periodontitis using the ligature method with or without P. gingivalis in NLRP3 knock out (KO) mice ( 18 – 20 ). Our results show that NLRP3 KO mice present an increased alveolar bone resorption and soft tissue destruction, as compared to WT mice in the absence of P. gingivalis , suggesting a protective role for NLRP3.…”

NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?

“…During the growth and development of bones, the NLRP3 inflammasome and its associated proteins have positive regulatory effects. Compared with NLRP3 +/+ mice, NLRP3 -/- mice have shorter stature, impaired long bone growth, and defective osteoblast differentiation and mineralization ( 45 ). ASC is an essential molecule in the osteoblast phenotype.…”

Actions of the NLRP3 and NLRC4 inflammasomes overlap in bone resorption

“…They reinforce the notion that the NLRP3 inflammasome is a key player in bone resorption in various pathological conditions, including exposures to polymethylmethacrylate particles, high RANKL concentrations, radiation, estrogen deficiency, continuous administration of parathyroid hormone, and autoinflammatory and autoimmune diseases 10,34,41,42,46,48,61‐63 . Although the current work was focused on bone resorption, it is worth noting that germline 4‐week‐old and 16‐week‐old Nlrp3 null male mice exhibited shorter stature and lower bone mass compared to WT controls, a phenotype explained by altered growth plate development and impaired osteogenesis as osteoclastogenesis was unaffected 64 . Thus, a possible contribution of the osteoblast lineage‐expressed NLRP3 to the phenotype described herein cannot be ruled out.…”