IRAK-M (IL-1 receptor associated kinase-M) is an endogenous inhibitor of intracellular signaling from both IL-1 receptor (IL-1R) and Toll-like receptors (TLRs)1.  Recently, our group found in collaboration with Agnes Vignery that IRAK-M-deficient mice develop osteoporosis spontaneously, and that this is associated with increased numbers of osteoclasts in the trabecular bones2.  These phenotypes of the IRAK-M deficient mice are consistent with previous observations that IL-1 and TLR ligands promote osteoclastogenesis in vitro and in vivo3; 4; 5; 6, and indicating a crucial role for IL-1R or TLRs in the osteogenesis.  Especially, the fact that the IRAK-M deficient mouse develops spontaneous osteoporosis implies that the osteoclast precursors in situ are constitutively enforced to differentiate into mature osteoclasts by IL-1 and/or TLR ligands.  Then, here, we will address a question; which ligand of IL-1R/TLRs is the most important factor for the constitutive promotion of osteoclastogenesis?  If such a ligand is identified, it would be a target of the therapy for osteoporosis.
    In this application, we will test if osteoporosis in the IRAK-M deficient mice can be reverted by the concomitant genetic defect of MyD88 or caspase-1.  If MyD88 deficiency rescues the bone phenotype in the IRAK-M -/- mice, the constitutive acceleration of the osteoclastogenesis in vivo through IL-1R/TLRs will be confirmed.  If caspase-1 deficiency reverts the osteoporosis, this implies that IL-1 signal is essential for the development of osteoporosis in the IRAK-/- mice.  In the follow-up to this pilot, we will examine the effect of further upstream factors, e.g. TLRs, ASC, NALP3 or Ipaf, to unravel the mechanism of constitutive acceleration of osteoclastogenesis by IL-1R/TLRs.