In adults, cells within the organ of Corti normally secrete soluble factors to suppress remodeling of cochlear bone by osteoclasts and osteoblasts. The importance of this crosstalk is evident in bone syndromes where these pathways are disrupted. For example, otosclerosis and osteogenesis imperfecta tarda are characterized by sensorineural, conductive, and mixed forms of hearing loss. Patients with fibrous dysplasia of bone have lesions containing dense fibro-cellular infiltrate and increased trabecular bone formation. FD is caused by activating mutations in the Gs G-protein coupled receptor signaling pathway, which increases cyclic adenosine monophosphate levels. As many as 20% of FD patients have hearing loss. Disrupted bone remodeling leading to the overgrowth of temporal bones is thought to contribute to this progressive hearing loss in FD patients, which also can be either conductive, sensorineural, or both. However, the traditional methods of discriminating conductive vs. sensorineural hearing loss require intact bone physical properties to make that distinction. Thus our goal was to elucidate the mechanisms responsible for hearing loss in fibrous dysplasia. In this study, we used a transgenic mouse model of increased Gs-GPCR signaling to better define the mechanisms by which FD causes hearing loss. The complexity of the GNAS locus and embryonic lethality of constitutively-active Gsa signaling preclude direct genetic modifications to introduce the classical GNAS mutations that cause fibrous dysplasia. Since GPCRs signal through a limited number of canonical pathways including Gs and Gi that ultimately regulate intracellular cAMP levels, we developed a method of inducing regulated Gs signaling in cells by engineered receptors such as RASSLs. RASSLs are powerful tools for studying GPCR signaling as they no longer respond to endogenous hormones but can be activated by synthetic small-molecule ligands. In addition, RASSLs are small genes easily expressed in constructs and transgenes allowing precise spatial and temporal regulation. RASSLs have proven to be useful for dissecting GPCR signaling in complex tissues including bone, brain, and heart. In addition, we consistently observed MMP-13 staining in the pericellular matrix and intracellular space, in addition to the bone matrix staining that is typically observed. This altered MMP-13 localization in the severe FD mice may indicate that Rs1 expression is associated with a protein processing defect or change in the localization of bone matrix proteins, and may account for a decrease in bone matrix maturation we observed previously in long bones. Surprisingly, while the FD-like lesions were easily identified in the bony structures surrounding the cochlea, the most severe lesions largely spared the cochlea itself. We speculate that this protection may result from the unique regulation of bone remodeling in the cochlea which is very limited relative to bone remodeling.