Role of Osteoblast Gi Signaling in Age-Related Bone Loss in Female Mice

Abstract

Age-related bone loss is an important risk factor for fractures in the elderly; it results from an imbalance in bone remodeling mainly due to decreased bone formation. We have previously demonstrated that endogenous G protein–coupled receptor (GPCR)-driven Gi signaling in osteoblasts (Obs) restrains bone formation in mice during growth. Here, we launched a longitudinal study to test the hypothesis that Gi signaling in Obs restrains bone formation in aging mice, thereby promoting bone loss. Our approach was to block Gi signaling in maturing Obs by the induced expression of the catalytic subunit of pertussis toxin (PTX) after the achievement of peak bone mass. In contrast to the progressive cancellous bone loss seen in aging sex-matched littermate control mice, aging female Col1(2.3)+/PTX+ mice showed an age-related increase in bone volume. Increased bone volume was associated with increased bone formation at both trabecular and endocortical surfaces as well as increased bending strength of the femoral middiaphyses. In contrast, male Col1(2.3)+/PTX+ mice were not protected from age-related bone loss. Our results indicate that Gi signaling markedly restrains bone formation at cancellous and endosteal bone surfaces in female mice during aging. Blockade of the relevant Gi-coupled GPCRs represents an approach for the development of osteoporosis therapies—at least in the long bones of aging women.

Co-stimulation of LPAR1 and S1PR1/3 increases the transplantation efficacy of human mesenchymal stem cells in drug-induced and alcoholic liver diseases

“…3b ). This finding was in line with recent reports that antagonism of LPAR 1 or Gi could protect cells from injuries induced by diabetes [ 26 ], hyperoxia [ 27 ], and ageing [ 28 ]. For S1P, all three subtypes of its receptor were detectable from the stem cell-isolated total RNA (Fig.…”

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

“…Using these methods Willingham et al ., (2010) and Ng et al ., (2016) reported yield loads for femur in female mice at 20 months of age at 16.5 and 19 N respectively 61 , 62 . Moreover, Saless et al ., (2010) also reported yield load of 14.1 N in 4 month old female mice; other studies have provided data close to this range 63 – 65 . It is evident therefore that the 11 N load applied to aged mouse bones in our study is much lower than would likely be required to generate any structural damage to the tibia.…”

Bone Status in a Mouse Model of Experimental Autoimmune-Orchitis

“…On the contrary, the Mycobacterium tuberculosis in CFA was inactivated before immunization and histomorphological evaluation did not reveal any accumulation of bacteria in the investigated bone tissue. In vitro and in vivo Bordetella pertussis toxin itself was even found to be beneficial regarding bone metabolism by blocking endogenous G protein-coupled receptor-driven G i -signaling in osteoblasts, and induced an increase in bone volume in aging female mice [37,38]. Summarizing, the actual reason for the significant alterations regarding bone status in the adjuvant group cannot finally be explained by the present study and needs to be elucidated by a future study.…”