Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that presents with painful, sterile inflammatory bone lesions. CRMO is often accompanied by psoriasis or inflammatory bowel disease (Crohn disease) suggesting a shared pathogenesis. Gene defects have been found in a subset of individuals with CRMO. Mutations in IL1RN, which encodes the interleukin-1 receptor antagonist (IL-1Ra), result in neonatal onset CRMO and pustulosis. Treatment of these infants with anakinra (recombinant IL-1Ra) results in prompt resolution of the inflammatory bone and skin lesions. This strongly implicated IL-12 in CRMO pathogenesis. Mutations in pstpip2 cause CRMO in a murine model. PSTPIP1, a closely related molecule interacts with pyrin as part of a macromolecular complex called the inflammasome that is critical to IL-12 processing, yet, the role of the IL-12 pathway in murine CRMO has yet to be determined. For the majority of individuals with CRMO, the genetic factors and immunologic pathway that are critical in disease initiation are unknown. There is a critical need to identify the inflammatory pathway(s) and disease trigger(s), so that we can not only improve treatment for CRMO but so that we can better understand inflammatory mediated bone disorders. Our long term goal is to determine the role of the identified immunologic pathways in the pathogenesis of the disorders that accompany CRMO, including psoriasis, psoriatic arthritis and inflammatory bowel disease, in order to develop improved therapies. Our hypothesis is that CRMO is triggered by an aberrant immune system response to microbial or other noxious stimuli. Our objective in this application is to identify genes that underlie the pathogenesis of CRMO, to further delineate critical inflammatory molecules required for bone inflammation and to evaluate the potential contribution of abnormal response(s) to microbes or other noxious stimuli as triggers of disease.
Our specific aims are to 1) define the pathways required for disease pathogenesis in a murine model of CRMO and to 2) determine if these inflammatory pathways are recapitulated in the disease pathogenesis of CRMO in humans. The experimental approach for aim 1 includes making double mutant cmo mice that lack critical innate immune system proteins to determine if they are required for disease;examining the response to cytokine blockade in vivo;examining the response of cmo immune cells to various innate immune system triggers both in vitro and in vivo;and by determining the role of proteins critical to inflammasome function in osteoclastogenesis. The experimental approach for aim 2 includes a family based genetic association study, homozygosity mapping in appropriate families, and in vitro studies to examine the innate immune response of leukocytes from CRMO patients to activators of the inflammasome. Taken together, these assays will provide critical insights into the inflammatory pathways important in CRMO.
Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder of the bone. Commonly, people with CRMO have associated inflammatory conditions including psoriasis or inflammatory bowel disease. Like psoriasis and inflammatory bowel disease, CRMO has a genetic component. In order to expand our knowledge about CRMO, psoriasis and inflammatory bowel disease, we are proposing studies aimed at identifying additional genes that can cause CRMO as well as studying what immunologic abnormalities are seen in individuals diagnosed with CRMO. This may ultimately help develop new ways to diagnose and treat not only CRMO but potentially also psoriasis and inflammatory bowel disease.
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