Abstract Hyper-parathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder in which patients present with parathyroid adenoma or carcinoma, renal cysts, and fibro-osseous tumors of the maxilla or mandible. HPT-JT is caused by loss of heterozygosity or inactivating mutations within the hyperparathyroidism 2 (HRPT2) gene that encodes the tumor suppressor parafibromin. As a core member of the Polymerase Associated Factors (PAF) complex, parafibromin binds to nuclear β-catenin and is known to associate with RNA Polymerase II to facilitate transcriptional initiation and elongation. Recently, the ability of parafibromin to associate with β-catenin and drive Wnt target gene transcription was found to be dependent on dephosphorylation by protein tyrosine phosphatase 2 (Shp2). Additionally, Bruton's Tyrosine Kinase (BTK) has been identified as a negative regulator of Wnt target gene transcription through interaction with parafibromin. Together, these findings suggest that the phosphorylation status of parafibromin may define its role as a transcriptional repressor or activator. Our objective is to determine how the phosphorylation status of parafibromin regulates Wnt target gene transcription. As Wnt is well known as a positive regulator of osteogenesis, which plays an important role during HPT-JT, it is also important to decipher the role parafibromin plays within osteoblast differentiation. Conditional deletion of Hrpt2 within mature osteoblasts using osteocalcin-driven Cre results in increased bone mineral density, cortical thickness, and overall stiffness of 3- and 6-month-old murine femurs. In addition, loss of Hrpt2 within mesenchymal progenitors using Dermo1-driven Cre results in embryonic lethality at approximately embryonic day 12.5. However, initial in vitro investigations assessing rates of mineralization and calcium deposition within Hrpt2-null osteoblasts show no significant changes as compared to wildtype controls. From these results, it is clear that parafibromin is essential for embryonic development and is a potential inhibitor of bone mass accrual, yet further investigation as to what genes are being occupied and regulated by parafibromin is needed. These findings will aid in the understanding of bone development and may provide insight into the pathogenesis of HPT-JT. Citation Format: Casey J. Droscha, Diegel Cassandra, Bart O. Williams. Insights into the pathogenesis of hyperparathyroidism-jaw tumor syndrome: Deciphering the role of Hrpt2 within bone development. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A66.