Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
J Bone Miner Res. 2021 Aug;36(8):1510-1520. doi: 10.1002/jbmr.4312. Epub 2021 Jun 4.
Bone 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 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and inhibits mammalian target of rapamycin complex 1 (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, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer binding protein α (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 origin. To determine whether circumventing the decrease in mTORC1 signaling in maturing osteoblasts attenuates the osteoblast and BMAT phenotype, phosphate-restricted mice with OSX-Cre -mediated haploinsufficiency of the mTORC1 inhibitor, TSC2, were generated. TSC2 haploinsufficiency in preosteoblasts/osteoblasts normalized bone volume and osteoblast number in phosphate-restricted mice and attenuated the increase in BMAT observed. Thus, acute phosphate restriction leads to decreased bone and increases BMAT by impairing mTORC1 signaling in osterix-expressing cells. © 2021 American Society for Bone and Mineral Research (ASBMR).
骨髓基质细胞（BMSCs）是多能细胞，可以分化为成骨细胞和脂肪细胞谱系的细胞。在几种情况下，骨髓脂肪组织（BMAT）与骨量之间存在显著的负相关关系，这表明 BMSCs 分化为骨髓脂肪细胞会使细胞偏离成骨细胞谱系，从而损害骨骼的结构和机械性能。生长中的小鼠磷酸盐限制会急性减少骨形成，阻止成骨细胞分化并增加 BMAT。为评估急性磷酸盐限制对细胞和分子基础的影响而进行的研究表明，它会急性增加成骨细胞中 5' 腺苷单磷酸激活蛋白激酶（AMPK）的磷酸化，并抑制哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号。这伴随着 BMSCs 中 Wnt10b 表达的减少。磷酸盐限制还促进 CXCL12 丰富的网状（CAR）细胞中关键脂肪生成转录因子过氧化物酶体增殖物激活受体γ（PPARγ）和 CCAAT 增强子结合蛋白α（CEBPα）的表达，CAR 细胞代表未分化的 BMSCs，是成年鼠骨骼中 BMAT 和成骨细胞的主要来源。与此一致，谱系追踪研究表明，在磷酸盐限制的小鼠中观察到的 BMAT 源自 CAR 细胞。为了确定在成熟成骨细胞中绕过 mTORC1 信号的减少是否会减轻成骨细胞和 BMAT 表型，生成了 OSX-Cre 介导的 mTORC1 抑制剂 TSC2 杂合不足的磷酸盐限制小鼠。成骨前体细胞/成骨细胞中的 TSC2 杂合不足可使磷酸盐限制小鼠的骨量正常化并减少成骨细胞数量，并减轻观察到的 BMAT 增加。因此，急性磷酸盐限制会通过损害成骨细胞中 osterix 表达细胞中的 mTORC1 信号，导致骨量减少和 BMAT 增加。2021 年美国骨骼与矿物质研究协会（ASBMR）。
