Phosphate restriction impairs mTORC1 signaling leading to increased bone marrow adipose tissue and decreased bone in growing mice

AbstractBone Marrow Stromal Cells (BMSCs) are multipotent cells that differentiate into cells of the osteogenic and adipogenic lineage. A striking inverse relationship between Bone Marrow Adipose Tissue (BMAT) and bone volume is seen in several conditions, suggesting that differentiation of BMSCs into bone marrow adipocytes diverts cells from the osteogenic lineage, thereby compromising the structural and mechanical properties of bone. Phosphate restriction of growing mice acutely decreases bone formation, blocks osteoblast differentiation and increases BMAT. Studies performed to evaluate the cellular and molecular basis for the effects of acute phosphate restriction demonstrate that it acutely increases AMPK phosphorylation and inhibits mTORC1 signaling in osteoblasts. This is accompanied by decreased expression of Wnt10b in BMSCs. Phosphate restriction also promotes expression of the key adipogenic transcription factors, PPAR γ and CEBPα, in CXCL12 Abundant Reticular (CAR) cells, which represent undifferentiated BMSCs and are the main source of BMAT and osteoblasts in the adult murine skeleton. Consistent with this, lineage tracing studies reveal that the BMAT observed in phosphate‐restricted mice is of CAR cell orig in.To determine whether circumventing the decrease in mTORC1 signaling inmaturing osteoblasts attenuates the osteoblast and BMAT phenotype, phosphate restricted mice with OSX ‐CreERT2‐mediated haploinsufficiency of the mTORC1 inhibitor, TSC2 were genera...

Source: Journal of Bone and Mineral Research - April 26, 2021 Category: Orthopaedics Authors: Frank C. Ko, Margaret M. Kobelski, Wanlin Zhang, Gina M. Grenga, Janaina S Martins, Marie B. Demay Tags: Original Article Source Type: research