Hypoxia‐Inducible Factor‐2α Signaling in the Skeletal System

Abstract

Hypoxia‐inducible factors (HIFs) are oxygen‐dependent heterodimeric transcription factors that mediate molecular responses to reductions in cellular oxygen (hypoxia). HIF signaling involves stable HIF‐β subunits and labile, oxygen‐sensitive HIF‐α subunits. Under hypoxic conditions, the HIF‐α subunit is stabilized, complexes with nucleus‐confined HIF‐β subunit, and transcriptionally regulates hypoxia‐adaptive genes. Transcriptional responses to hypoxia include altered energy metabolism, angiogenesis, erythropoiesis, and cell fate. Three isoforms of HIF‐α—HIF‐1α, HIF‐2α, and HIF‐3α—are found in diverse cell types. HIF‐1α and HIF‐2α serve as transcriptional activators, whereas HIF‐3α restricts HIF‐1α and HIF‐2α. The structure and isoform‐specific functions of HIF‐1α in mediating molecular responses to hypoxia are well established across a wide range of cell and tissue types. The contributions of HIF‐2α to hypoxic adaptation are often unconsidered if not outrightly attributed to HIF‐1α. This review establishes what is currently known about the diverse roles of HIF‐2α in mediating the hypoxic response in skeletal tissues, with specific focus on development and maintenance of skeletal fitness. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The impact of diabetes, anemia, and renal function in the relationship between osteoporosis and fasting blood glucose among Taiwanese women: a cross-sectional study

“…Hypoxia-inducible factors (HIFs), crucial in the cellular response to hypoxia [ 51 ], with HIF1-α and HIF2-α may impact osteoblast and osteoclast functions in bone homeostasis [ 52 , 53 ]. Iron deficiency directly or indirectly impedes osteoblastic differentiation and promotes osteoclastic differentiation by leading to hypoxia-induced increases in HIF-1/2α expression and a reduction in active vitamin D levels [ 54 ]. Adequate nutrient intake and normal red blood cell production generally support bone health in non-anemic individuals, but factors such as hormonal balance and physical activity can also play significant roles.…”

Angelica sinensis polysaccharides promote extramedullary stress erythropoiesis via ameliorating splenic glycolysis and EPO/STAT5 signaling-regulated macrophages

“…The expression of genes involved in erythropoiesis and glycolytic metabolism, which are regulated by HIFs, is enhanced in hypoxic environments. Acute hypoxic responses are associated with HIF1α, while chronic hypoxia responses are linked to HIF2α [29]. Knock down HIF2α gene seriously impaired erythroid progenitors in the bone marrow and spleen.…”

Iron Deficiency and Iron Deficiency Anemia: Potential Risk Factors in Bone Loss

“…Hypoxia-inducible factors (HIFs), the heterodimeric transcription factors composed of an oxygen-sensitive α subunit and a stable β subunit, are critical mediators of the cellular response to hypoxia [ 96 ]. HIF1-α and HIF2-α are proposed to contribute to the functions of osteoblasts and osteoclasts in bone homeostasis [ 97 , 98 ], which can potentially be attributed to the hypoxic condition in bone microenvironments, such as the endosteal areas of bone medullary cavity and the epiphyseal growth plate [ 99 ].…”