Hypoxia, HIFs and bone development

Abstract

Oxygen is not only an obviously important substrate, but it is also a regulatory signal that controls expression of a specific genetic program. Crucial mediator of the adaptive response of cells to hypoxia is the family of Hypoxia-Inducible Transcription Factors (HIFs).The fetal growth plate, which is an avascular structure of mesenchymal origin, has a unique out-in gradient of oxygenation. HIF-1alpha is necessary for chondrogenesis in vivo by controlling a complex homeostatic response that allows chondrocytes to survive and differentiate in a hypoxic environment. Moreover, HIFs are also essential in osteogenesis and joint development. This brief Perspective summarizes the critical role of HIFs in endochondral bone development.

Figure 1. Diagram of the HIF-1α pathway

In normoxia prolyl-hydroxylases (PHDs) hydroxylates prolyns 402 and 564 in the O₂ –dependent degradation domain (ODDD) of HIF-1α, leading to its proteosomal degradation mediated by the von Hippel-Lindau (VHL) ubiquitine ligase. Also the factor inhibiting HIF (FIH) can hydroxylate HIF-1α on asparagine 803 in its carboxy-terminal transactivation domain (C-TAD), leading to transcriptional inactivation. When HIF is stabilized in normoxia, a plethora of genes that contain hypoxia responsive elements (HRE, 5'-RCGTG-3') are expressed. Among the hypoxia-induced genes there are microRNAs, genes involved in metabolism, angiogenesis, erythropoiesis, chondrocyte differentiation and collagen matrix.

Figure 2. Schematic representation of the fetal growth plate

Mesenchymal cells differentiate into round proliferative chondrocytes and when they divide are piled up in a layer of columnar proliferative chondrocytes. Both layers produce collagen type II. The latest chondrocytes are the hypertrophic ones that express collagen type X and mineralize their matrix. When hypertrophic chondrocytes undergo apoptosis, the space is invaded by blood vessels and colonized by osteoblasts, which produce the primordial trabecular bone, also called primary spongiosa. The most hypoxic areas in the growth plate are shown in red.