Fibrous dysplasia (FD) is a mosaic disorder caused by activating Gαs variants. Skeletal stem cells give rise to abnormal osteoprogenitors, resulting in fibro-osseous lesions with prominent osteoclastogenesis. Gαs variants are reliably demonstrated in osteoprogenitors, however involvement in other skeletal cell types is not well-characterized. We evaluated human specimens to investigate Gαs variant expression in chondrocytes and osteoclasts, two prominent cell types in FD lesions. Seven of 20 bone specimens had cartilage present in addition to typical fibrous tissue. Droplet digital polymerase chain reaction detected variant Gαs DNA in all cartilaginous samples and most fibrous tissue, in similar proportions. Variant-specific staining of Gαs mRNA using BaseScope demonstrated variant expression in approximately 14% of chondrocytes. Approximately 3.4% of osteoclasts expressed variants, below the 5% assay false positivity rate. To further investigate this surprising finding, primary murine osteoclast cultures were treated with dibutyryl-cAMP to mimic Gαs activation. Treatment attenuated osteoclastogenesis, diminished resorption, and toxic at high doses. To further investigate the lack of osteoclast variant expression, we isolated pre-osteoclastic monocytes from patient whole blood samples. Monocytes demonstrated an average variant allele frequency of ∼20%, with strong correlations to overall FD burden. We demonstrate that chondrogenesis is common in FD and arises directly from Gαs variants. While osteoclasts play a pivotal role in FD pathogenesis, our results surprisingly indicate that direct expression of Gαs variants may impair osteoclastogenesis. This study provides key insights into FD as a complex disorder driven by interplay of multiple cellular lineages and will inform development of targeted therapies.
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