Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104.
Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2416004121. doi: 10.1073/pnas.2416004121. Epub 2024 Nov 27.
Estrogen deficiency, which is linked to various pathological conditions such as primary ovarian insufficiency and postmenopausal osteoporosis, disrupts the delicate balance between bone formation and resorption. This imbalance leads to bone loss and an increased risk of fractures, primarily due to a significant reduction in trabecular bone mass. Trabecular osteoblasts, the cells responsible for bone formation within the trabecular compartment, originate from skeletal progenitors located in the bone marrow. The microenvironment of the bone marrow contains hypoxic (low oxygen) regions, and the hypoxia-inducible factor-2α (HIF2) plays a crucial role in cellular responses to these low-oxygen conditions. This study demonstrates that the loss of HIF2 in skeletal progenitors and their derivatives during development enhances trabecular bone mass by promoting bone formation. More importantly, PT2399, a small molecule that specifically inhibits HIF2, effectively prevents trabecular bone loss in ovariectomized adult mice, a model for estrogen-deficient bone loss. Both the genetic and pharmacological approaches result in an increase in osteoblast number, which is linked to the expansion of the pool of skeletal progenitor cells. This expansion either by loss or inhibition of HIF2 uncovers a pivotal mechanism for increasing osteoblast numbers and bone formation, resulting in greater trabecular bone mass.
雌激素缺乏与多种病理状况有关，如原发性卵巢功能不全和绝经后骨质疏松症，破坏了骨形成和吸收之间的微妙平衡。这种失衡导致骨丢失和骨折风险增加，主要是由于小梁骨量的显著减少。小梁成骨细胞是负责小梁骨形成的细胞，起源于位于骨髓中的骨骼祖细胞。骨髓的微环境包含缺氧（低氧）区域，缺氧诱导因子-2α（HIF2）在细胞对这些低氧条件的反应中起着至关重要的作用。这项研究表明，在发育过程中，骨骼祖细胞及其衍生物中 HIF2 的缺失通过促进骨形成增强了小梁骨量。更重要的是，小分子化合物 PT2399 特异性抑制 HIF2，可有效防止去卵巢成年小鼠（雌激素缺乏性骨丢失模型）的小梁骨丢失。基因敲除和药理学方法都导致成骨细胞数量增加，这与骨骼祖细胞池的扩大有关。通过 HIF2 的缺失或抑制来扩大骨骼祖细胞池，揭示了增加成骨细胞数量和骨形成的关键机制，从而导致小梁骨量增加。
