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P&F Grant Awards

Year 3

Grant # 4

NLRP3 Expression in Myeloid Cells is Sufficient to Stimulate Bone Resorption

PI: Gabriel Mbalaviele, Ph.D.,


Specific Aims

The Nod-like receptor protein 3 (NLRP3) inflammasome is an intracellular protein complex responsible for the maturation of several members of interleukin (IL)-1 family, including the osteotropic factors, IL-1b and IL-18. NLRP3 is also involved in the inactivation of poly(ADP-ribose) polymerase 1 (PARP1), a negative regulator of osteoclast (OC) development [1-3]. NLRP3 is activated by danger-associated molecular patterns (DAMPs) such as crystals, wear particles and degradation products of endogenous components of the extracellular matrix (ECM) [4].

Trafficking of both organic and inorganic degradation products from bone ECM through bone-resorbing OC to the extracellular milieu is a critical step during bone resorption [5, 6]. This process enables OC to excrete degraded matrix components while digging deep into bone and maintaining an enclosed resorption site. Thus, the products of bone resorption are potential activators of NLRP3 in OC. Interestingly, patients with neonatal-onset multisystemic inflammatory disease (NOMID), a condition linked to NLRP3-activating mutations [7], exhibit skeletal malformations and low bone mass in up to 60% of the cases [8]. Our own preliminary data demonstrates that mice globally expressing a constitutively active NLRP3 mutant, which model the human NOMID syndrome, have severely decreased bone mass and increased bone resorption, leading to stunted post-natal growth. Thus, there is now strong evidence from human and mouse genetics that NLRP3 is critically involved in normal skeletal homeostasis. However, little if any is known about the role of NLRP3 in bone homeostasis. We hypothesize that 1) NLRP3 activation in myeloid cells is important for bone resorption, and 2) bone ECM degradation products function as endogenous DAMPs for NLRP3 in the OC lineage. Accordingly, we propose to test these hypotheses in the following Specific Aims.

  1. Determine whether NLRP3 activation in myeloid cells is sufficient to stimulate bone resorption.
  2. Identify bone-relevant DAMPs and study the regulatory mechanisms of NLRP3 activation in OC.
The peri-natal lethality of pups globally expressing mutant NLRP3 hampers the efforts to elucidate the role of NLRP3 in bone. To gain further insight into the role of NLRP3 in bone resorption, we propose to use mice in which the expression of mutant NLRP3 is restricted to the myeloid cell lineage. These mice are available to us from our collaborator, Dr. Hoffman (Univ of Calfornia at San Diego). The funding requested will support the characterization of these mice to advance this project to the point where a comprehensive data package is generated for future NIH applications. We anticipate that these studies will unravel a novel communication mode among bone cells and with their environment via NLRP3, and reveal this upstream component of the IL-1 family and PARP1 pathways as a potential new target for therapeutic intervention in bone diseases.