Loss of Progranulin Expression Decreases NLRP3 Inflammasome-Mediated Inflammation and Enhances Bone Anabolism

Progranulin (PGRN), a glycosylated protein, is expressed in most tissues, including bones, and its level is elevated in the serum and joints of individuals with inflammatory bone loss disorders such as rheumatoid arthritis (RA). Previously, using global and macrophage-specific Grn deletion mice, we demonstrated that loss of PGRN protects against age-related bone loss selectively in females, suggesting a sex-dependent role for macrophage-derived PGRN in skeletal homeostasis. Here, we investigated the role of PGRN in the regulation of macrophage-mediated inflammation and bone formation. Immune-phenotyping revealed that Grn ^-/- vs. WT mice exhibited higher percentages of Mac2^Hi subsets in both sexes. Transcriptomic analysis of Mac2^Hi vs. Mac2^Lo from WT mice showed reduced expressed expression of Nlrp3 and Il1β at baseline in both sexes. Further, Grn ^-/- vs. WT M-CSF-dependent macrophages (BMMs) revealed decreased expression of Nlrp3 and Il1β following LPS challenge in vivo in both sexes. Consistent with this, Grn ^-/- mice displayed markedly reduced IL-1β production in serum and paw joints, and attenuated bone erosion in the STA-induced RA model, indicating altered NLRP3 inflammasome signaling in Grn ^-/- mice. Notably, PGRN deficiency enhances the osteoanabolic capacity of macrophages: female Grn ^-/- BMMs potentiated osteogenic differentiation of mesenchymal stem cells, and in vivo, Grn ^-/- females exhibited higher trabecular bone formation in response to intermittent PTH. Collectively, PGRN deficiency in BMMs is negatively associated with Nlrp3 expression and IL-1β production and causes reduced inflammation and bone erosion in mice subjected to STA-induced RA. Furthermore, PGRN limits the bone-anabolic action of PTH in a female sex-specific manner.