NLRP12 provides a critical checkpoint for osteoclast differentiation

Jennifer L. Krauss, Rong Zeng, Cynthia L. Hickman-Brecks, Justin E. Wilson, Jenny P.Y. Ting, Deborah V. Novack

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The alternative or noncanonical nuclear factor kappa B (NF-κB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-κB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-κB-induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro observations dovetail with our in vivo findings that NLRP12 deficiency leads to enhanced OC numbers accompanied by a significant decline in bone mass under physiological conditions. Consistent with the basal bone phenotype, we also observed an enhanced osteolytic response following RANKL injection over the calvaria of NLRP12-deficient chimeric mice compared with wild-type control mice. Thus, modulation of NLRP12 levels controls alternative NF-κB signaling in OC precursors, altering bone homeostasis and osteolytic responses.

Original languageEnglish
Pages (from-to)10455-10460
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
DOIs
StatePublished - Aug 18 2015

Keywords

  • Alternative NF-κB
  • Bone
  • NLRP12
  • Osteoclast

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