Project Summary / Abstract A healthy dentition with appropriately functioning teeth is essential for maintaining quality of life (QOL). Disorders involving tooth eruption are prevalent, as high as 2–4% in permanent molars alone. Multiple molars are involved in severe cases such as rare genetic conditions of primary failure of tooth eruption (PFE) or, more commonly, bisphosphonate-induced arrest of tooth eruption in pediatric patients, which significantly compromise the patients' ability to chew effectively. Because these molars do not response well to conventional orthodontic approaches, innovative adjuvant therapies are needed to restore tooth eruption of affected molars for better clinical outcomes. Tooth eruption is regulated by cells in the dental follicle (DF) surrounding developing molars, which express parathyroid hormone-related protein (PTHrP) and its cognate PTH/PTHrP receptor (PTH1R). Disruption of autocrine PTHrP-PTH1R signaling in PTHrP+ DF cells causes failure of tooth eruption in murine molars that closely recapitulates the human PFE condition. Salt inducible kinases (SIKs) are an essential downstream effector of PTH1R-cAMP/PKA signaling in bone, in which cAMP- regulated PKA-dependent SIK inhibition is a key component of the anabolic actions of PTH. Small molecules SIK inhibitors hold promise as a novel therapeutic strategy to enhance cAMP-induced signals in a receptor- independent manner. In this proposal, we hypothesize that activation of the PTH1R signaling pathway by direct SIK inhibition can restore defective tooth eruption of molars in mouse models of genetically and pharmacologically induced tooth eruption disorders. In Aim 1, we will identify the roles of SIKs in PTHrP+ dental follicle cells in tooth eruption. We hypothesize that SIKs regulate osteoblast cell fates of PTHrP+ DF cells and tooth eruption. We will define the function of SIK2/SIK3 by conditionally deleting these genes in PTHrP+ DF cells at the onset of tooth eruption. We will define short-term and long-term alterations in tooth eruption and tooth root structures of mutant molars using histological and 3D microCT analyses. In Aim 2, we will determine the effects of SIK inhibition in rescuing PFE in molars. We hypothesize that SIK inhibition rescues failure of tooth eruption in molars genetically caused by PTH1R deficiency. We will determine the effects of SIK inhibition in a mouse model of PFE, in which PTH1R is conditionally deleted in PTHrP+ DF cells at the onset of tooth eruption. We will investigate whether PFE phenotypes can be rescued genetically by a concomitant loss of SIK2/SIK3, and pharmacologically by SIK inhibitor YKL-05-099. In Aim 3, we will define PTHrP as a bisphosphonate target and effects of SIK inhibitors in rescuing tooth eruption. We hypothesize that PTHrP- PTH1R signaling is altered in PTHrP+ DF cells in response to zoledronic acid (ZOL), and ZOL-induced arrest of tooth eruption in molars can be rescued by SIK inhibitors. We will treat ZOL-...