Mendoza Sarah V, Murugesh Deepa K, Christiansen Blaine A, Genetos Zoe O, Loots Gabriela G, Genetos Damian C, Yellowley Clare E
Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine University of California Davis Davis CA USA.
Lawrence Livermore National Laboratories Physical and Life Sciences Directorate Livermore CA USA.
JBMR Plus. 2023 Feb 17;7(4):e10724. doi: 10.1002/jbm4.10724. eCollection 2023 Apr.
Molecular oxygen levels vary during development and disease. Adaptations to decreased oxygen bioavailability (hypoxia) are mediated by hypoxia-inducible factor (HIF) transcription factors. HIFs are composed of an oxygen-dependent α subunit (HIF-α), of which there are two transcriptionally active isoforms (HIF-1α and HIF-2α), and a constitutively expressed β subunit (HIFβ). Under normoxic conditions, HIF-α is hydroxylated via prolyl hydroxylase domain (PHD) proteins and targeted for degradation via Von Hippel-Lindau (VHL). Under hypoxic conditions, hydroxylation via PHD is inhibited, allowing for HIF-α stabilization and induction of target transcriptional changes. Our previous studies showed that deletion in osteocytes ( ) resulted in HIF-α stabilization and generation of a high bone mass (HBM) phenotype. The skeletal impact of HIF-1α accumulation has been well characterized; however, the unique skeletal impacts of HIF-2α remain understudied. Because osteocytes orchestrate skeletal development and homeostasis, we investigated the role of osteocytic HIF-α isoforms in driving HBM phenotypes via osteocyte-specific loss-of-function and gain-of-function HIF-1α and HIF-2α mutations in C57BL/6 female mice. Deletion of or in osteocytes showed no effect on skeletal microarchitecture. Constitutively stable, degradation-resistant HIF-2α (HIF-2α cDR), but not HIF-1α cDR, generated dramatic increases in bone mass, enhanced osteoclast activity, and expansion of metaphyseal marrow stromal tissue at the expense of hematopoietic tissue. Our studies reveal a novel influence of osteocytic HIF-2α in driving HBM phenotypes that can potentially be harnessed pharmacologically to improve bone mass and reduce fracture risk. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
分子氧水平在发育和疾病过程中会发生变化。对氧生物利用度降低（缺氧）的适应是由缺氧诱导因子（HIF）转录因子介导的。HIF由一个氧依赖性α亚基（HIF-α，有两种转录活性异构体，即HIF-1α和HIF-2α）和一个组成性表达的β亚基（HIFβ）组成。在常氧条件下，HIF-α通过脯氨酰羟化酶结构域（PHD）蛋白发生羟基化，并通过冯·希佩尔-林道（VHL）蛋白靶向降解。在缺氧条件下，PHD介导的羟基化受到抑制，使得HIF-α得以稳定，并诱导靶基因转录变化。我们之前的研究表明，骨细胞中的（ ）缺失会导致HIF-α稳定，并产生高骨量（HBM）表型。HIF-1α积累对骨骼的影响已得到充分表征；然而，HIF-2α对骨骼的独特影响仍未得到充分研究。由于骨细胞协调骨骼发育和内环境稳定，我们通过C57BL/6雌性小鼠中骨细胞特异性功能丧失和功能获得的HIF-1α和HIF-2α突变，研究了骨细胞HIF-α异构体在驱动HBM表型中的作用。骨细胞中（ ）或（ ）的缺失对骨骼微结构没有影响。组成型稳定、抗降解的HIF-2α（HIF-2α cDR），而非HIF-1α cDR，会使骨量显著增加，增强破骨细胞活性，并以造血组织为代价使干骺端骨髓基质组织扩张。我们的研究揭示了骨细胞HIF-2α在驱动HBM表型中的新影响，这可能在药理学上被利用来增加骨量和降低骨折风险。© 2023作者。由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
