Characterization of OGFRL1 Knockout Mice

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The study of rare diseases has provided insights into normal human physiology and has led to strategies to prevent and treat common diseases. Cherubism (OMIM#118400) is an autosomal dominant form of fibrous dysplasia of the jaws characterized by maxillary and mandibular bone destruction caused by fibrous- inflammatory lesions. Currently, SH3-domain binding protein 2 (SH3BP2) is the only gene responsible for cherubism. However, we have identified new autosomal recessive cherubism patients who do not have mutations in SH3BP2 in consanguineous families from Syria and India. To identify novel cherubism genes, we performed whole exome sequencing and discovered homozygous loss-of-function mutations in the opioid growth factor receptor-like 1 (OGFRL1) gene of the affected members. Preliminary results showed that OGFRL1-knockdown increases cellular sensitivity to increase TNF-alpha production in a monocyte/macrophage cell line RAW264.7. The knockdown RAW264.7 cells also showed increased responsiveness to the receptor activator of nuclear factor-kappa B ligand (RANKL), resulting in increased formation of osteoclasts. Therefore, we propose that OGFRL1 is a novel negative regulator of macrophage activation and osteoclast differentiation to regulate the susceptibility to bone loss. Our overall hypothesis is that loss-of-function of OGFRL1 is responsible for a recessive form of cherubism and that OGFRL1 has yet unknown functions in regulating bone mass. Specific aims are: Aim 1) Determine whether OGFRL1 knockout mice recapitulate the phenotype of humans with OGFRL1 mutations. Aim 2) Determine whether OGFRL1 regulates bone loss in a periodontitis model. Aim 3) Determine whether OGFRL1 regulates bone loss in a rheumatoid arthritis model. We will establish OGFRL1 as a new gene responsible for cherubism and explore whether OGFRL1 is a new regulator of bone resorption in common inflammatory bone diseases. These studies will provide new insights into the etiology of cherubism and identify new pathways for the treatment of periodontal diseases and rheumatoid arthritis.