Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA.
Department of Biology, Stanford University, Stanford, CA, USA.
J Bone Miner Res. 2020 Oct;35(10):2004-2014. doi: 10.1002/jbmr.4091. Epub 2020 Jul 6.
Skeletal stem/progenitor cells (SSPC) are critical regulators of bone homeostasis by providing a continuous supply of osteoblasts throughout life. In response to inductive signals, SSPC proliferate before osteoblast differentiation. Proliferation requires the duplication of all cellular components before cell division. This imposes a unique biosynthetic requirement for amino acids that can be used for biomass production. Thus, the ability to sense and respond to amino acid availability is likely a major determinant for proliferation. Using a cellular and genetic approach, we demonstrate the amino acid sensor GCN2 is required to support the robust proliferative capacity of SSPC during bone homeostasis. GCN2 ablation results in decreased postnatal bone mass due primarily to reduced osteoblast numbers. Decreased osteoblast numbers is likely attributed to reduced SSPC proliferation as loss of GCN2 specifically affected proliferation in cultured bone marrow stromal cells (BMSCs) without impacting osteoblast differentiation in vitro. Mechanistically, GCN2 regulates proliferation by increasing amino acid uptake downstream of the transcriptional effector ATF4. Collectively, these data suggest amino acid sensing through the GCN2/ATF4 pathway is indispensable for robust SSPC proliferation necessary for bone homeostasis. © 2020 American Society for Bone and Mineral Research.
骨骼干/祖细胞（SSPC）通过在整个生命周期中提供持续的成骨细胞供应来充当骨内稳态的关键调节因子。响应诱导信号后，SSPC 在成骨细胞分化前增殖。增殖需要在细胞分裂前复制所有细胞成分。这对可用于生物量生产的氨基酸提出了独特的生物合成要求。因此，感知和响应氨基酸可用性的能力可能是增殖的主要决定因素。我们通过细胞和遗传方法证明，氨基酸传感器 GCN2 是支持 SSPC 在骨内稳态期间强大增殖能力所必需的。GCN2 的缺失导致出生后骨量减少，主要是由于成骨细胞数量减少。成骨细胞数量的减少可能归因于 SSPC 增殖减少，因为 GCN2 的缺失特异性地影响了培养的骨髓基质细胞（BMSC）中的增殖，而不会影响体外成骨细胞分化。从机制上讲，GCN2 通过增加转录效应物 ATF4 下游的氨基酸摄取来调节增殖。总的来说，这些数据表明，通过 GCN2/ATF4 途径感知氨基酸对于骨内稳态所需的强大 SSPC 增殖是必不可少的。 © 2020 美国骨骼与矿物质研究协会。
