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Loss of Adenylyl Cyclase 6 in Leptin Receptor?Expressing Stromal Cells Attenuates Loading?Induced Endosteal Bone Formation

ABSTRACT: ABSTRACT Bone marrow stromal/stem cells represent a quiescent cell population that replenish the osteoblast bone?forming cell pool with age and in response to injury, maintaining bone mass and repair. A potent mediator of stromal/stem cell differentiation in vitro and bone formation in vivo is physical loading, yet it still remains unclear whether loading?induced bone formation requires the osteogenic differentiation of these resident stromal/stem cells. Therefore, in this study, we utilized the leptin receptor (LepR) to identify and trace the contribution of bone marrow stromal cells to mechanoadaptation of bone in vivo. Twelve?week?old Lepr?cre;tdTomato mice were subjected to compressive tibia loading with an 11?N peak load for 40?cycles, every other day for 2?weeks. Histological analysis revealed that Lepr?cre;tdTomato+ cells arise perinatally around blood vessels and populate bone surfaces as lining cells or osteoblasts before a percentage undergo osteocytogenesis. Lepr?cre;tdTomato+ stromal cells within the marrow increase in abundance with age, but not following the application of tibial compressive loading. Mechanical loading induces an increase in bone mass and bone formation parameters, yet does not evoke an increase in Lepr?cre;tdTomato+ osteoblasts or osteocytes. To investigate whether adenylyl cyclase?6 (AC6) in LepR cells contributes to this mechanoadaptive response, Lepr?cre;tdTomato mice were further crossed with AC6fl/fl mice to generate a LepR+ cell?specific knockout of AC6. These Lepr?cre;tdTomato;AC6fl/fl animals have an attenuated response to compressive tibia loading, characterized by a deficient load?induced osteogenic response on the endosteal bone surface. This, therefore, shows that Lepr?cre;tdTomato+ cells contribute to short?term bone mechanoadaptation. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

SUBMITTER: Riffault M

PROVIDER: S-EPMC7657397 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION: Longitudinal studies on the age-related bone loss in men concerns the decrease in areal bone mineral density (aBMD), which can be qualified as "apparent bone loss" because it does not reflect the change in bone mineral content (BMC). Loss of BMC can be referred to as "net bone loss" because it does not take into account the morphological basis of the bone loss (decreased periosteal apposition; endosteal bone loss, i.e. bone loss on the trabecular, endocortical and intracortical surfaces). The aim of this study was to assess age-related apparent net and endosteal bone loss as well as their morphological basis and age-related changes during a prospective follow-up in a large cohort of elderly men. METHODS: This analysis was performed in 725 men aged 51-85 at baseline who were followed up for 90 months. RESULTS: Bone densitometry was carried out at the lumbar spine, hip and whole body by using the HOLOGIC QDR1500 device and at the distal forearm by using the Osteometer DTX100 device. Sixty-five men who abandoned the study after the first examination were older and had lower aBMC at most sites of measurement. Apparent bone loss was significant at the hip, distal forearm and whole body. Net bone loss was also significant at these sites, except for the femoral neck. Periosteal expansion was significant at all sites of measurement. Apparent and net bone loss accelerated with age, whereas the rate of periosteal expansion remained stable. At the distal radius and ulna, endosteal bone loss accelerated with age, whereas the rate of periosteal apposition remained stable. CONCLUSION: In a large cohort of elderly men, age-related apparent bone loss (aBMD) at the hip, distal forearm and whole body was determined by the net bone loss (BMC), except for the femoral neck. Apparent and net bone loss accelerated with age, whereas the periosteal expansion rate (bone widening) remained constant. At the distal forearm, age-related acceleration of the apparent bone loss was determined by the higher endosteal bone loss, whereas the periosteal apposition rate (estimated mass of deposited bone) remained constant.

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Loss of Adenylyl Cyclase 6 in Leptin Receptor?Expressing Stromal Cells Attenuates Loading?Induced Endosteal Bone Formation

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