Loss of the nutrient sensor TAS1R3 leads to reduced bone resorption

Abstract

The taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors participates in monitoring energy and nutrient status. TAS1R member 3 (TAS1R3) is a bi-functional protein that recognizes amino acids such as L-glycine and L-glutamate or sweet molecules such as sucrose and fructose when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively. It was recently reported that deletion of TAS1R3 expression in Tas1R3 mutant mice leads to increased cortical bone mass but the underlying cellular mechanism leading to this phenotype remains unclear. Here, we independently corroborate the increased thickness of cortical bone in femurs of 20-week-old male Tas1R3 mutant mice and confirm that Tas1R3 is expressed in the bone environment. Tas1R3 is expressed in undifferentiated bone marrow stromal cells (BMSCs) in vitro and its expression is maintained during BMP2-induced osteogenic differentiation. However, levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) are unchanged in the serum of 20-week-old Tas1R3 mutant mice as compared to controls. In contrast, levels of the bone resorption marker collagen type I C-telopeptide are reduced greater than 60% in Tas1R3 mutant mice. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and their expression levels positively correlate with differentiation status. Collectively, these findings suggest that high bone mass in Tas1R3 mutant mice is due to uncoupled bone remodeling with reduced osteoclast function and provide rationale for future experiments examining the cell-type-dependent role for TAS1R family members in nutrient sensing in postnatal bone remodeling.

Amino acids as signaling molecules modulating bone turnover

“…Moreover, stimulation of ERK phosphorylation by glutamate is consistent with umami taste receptors being present in BMSCs, as has been shown by others (23,24) . Work by a number of investigators suggests that these receptors play a role as cellular energy sensors, and activation or knocking out of these receptors can alter both adiposity and bone mass in vivo (15,23,25) . How these taste receptors interact with other AA sensors on BMSCs is not known.…”

“…How these taste receptors interact with other AA sensors on BMSCs is not known. However these receptors have also been recently shown to be present in osteoclasts suggesting a role in bone turnover (26) .…”

The role of GPCRs in bone diseases and dysfunctions

“…Additional phenotypes were validated in mouse models, in which deletion of Gababr1 , 111 Gprc6a , 112,113 and Grm1 114 reduced mouse BMD, while Tas1r3 deficiency impaired osteoclast function, resulting in reduced bone resorption and increased bone mass. 115,116 Gababr1 -null mice reduce BMD primarily through negatively regulating BMP and upregulating RANKL to affect bone remolding, 111 while the effects of Gprc6a deletion were primarily caused by defective osteoblast-mediated bone mineralization. 112,113 Grm1 knockout mice exhibit enhanced bone maturation, marked by premature growth plate fusion, shortened long bones, and lower BMD 114 (Table 1).…”

On the Emerging Role of the Taste Receptor Type 1 (T1R) Family of Nutrient-Sensors in the Musculoskeletal System

“…The function of T1R family members in several non-gustatory systems has been summarized previously [ 2 , 18 ]. However, we are particularly struck by several recent reports highlighting T1R family members in the musculoskeletal system [ 19 , 20 , 21 , 22 ] and wish to briefly review these findings in the context of the musculoskeletal diseases sarcopenia and osteoporosis, which are major public health problems among the elderly that affect locomotion, activities of daily living, and quality of life [ 23 ].…”