Jonathan W. Lowery, Ph.D.
Medicine and Health Sciences
Current therapies for low bone mass consist of inhibiting osteoclast activity or increasing the PTH or Wnt signaling pathways. These approaches have significant drawbacks that limit their use in specific patient populations and/or negatively impact patient compliance with therapy. Developing improved therapies requires diversifying our understanding of the mechanisms underlying postnatal bone remodeling by examining lesser-known signaling pathways. One such pathway is the taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors, which participates in monitoring energy and nutrient status. Previous work reported that global deletion of TAS1R member 3 (TAS1R3), which is a bi-functional protein that recognizes amino acids or sweet molecules when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively, leads to increased cortical bone mass. Here, we corroborate the increased thickness of cortical bone in Tas1R3 knockout mice and confirm that Tas1R3 is expressed in the bone environment. Quantification of serum bone turnover markers indicate that this phenotype is likely due to uncoupled bone remodeling, with levels of the bone resorption marker CTx being reduced greater than 60% in Tas1R3 mutant mice; no changes were observed in levels of the bone formation marker PINP. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and RAW264.7 cells following RANKL-mediated differentiation. These findings suggest that osteoclast function and/or differentiation may be altered in the absence of Tas1R3 expression. To test this, we quantified bone-specific expression of Rankl and determined the Rankl:Opg ratio; no differences were observed between control and Tas1R3 knockout mice in these analyses. In vitro studies examining further downstream effectors of TAS1R2:3 in response to saccharin and receptor antagonist gurmarin are currently underway. Collectively, our findings provide the first demonstration that nutrient monitoring by TAS1R3 is essential for normal bone resorption in vivo.
Copyright 2017 all authors
Weinstein, Nicholas; Eaton, Michael S.; Shively, Stephen R.; Davis, Hannah M; Plotkin, Lillian; and Lowery, Jonathan W. Ph.D., "Nutrient Sensing by Tas1R Proteins is Required for Normal Bone Resorption" (2017). MU-COM Research Day. 54.