Extracellular matrix genes as hypoxia-inducible targets

Abstract

Low oxygen tension, i.e., hypoxia, is a pathophysiological component involved in many human disorders but is also a critically important phenomenon in normal development and differentiation. The ability of cells to survive under hypoxia or to adapt to it depends on a family of hypoxia-inducible transcription factors (HIFs) that induce the expression of a number of genes involved in hematopoiesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, and extracellular matrix homeostasis. We introduce here the recently identified molecular mechanisms responsible for the oxygen-dependent stability and activity of HIF, after which we focus on extracellular matrix genes as HIF targets. The vital role of the hypoxia response pathway in chondrogenesis and joint development is then discussed.

Fig. 1

Regulation of the stability and activity of hypoxia-inducible transcription factor-1α (HIF-1α) by oxygen-dependent hydroxylation. Under normoxic conditions, HIF-1α is hydroxylated by HIF prolyl 4-hydroxylases (HIF-P4H) and factor inhibiting HIF (FIH). Hydroxylation of one or two specific prolines of the oxygen-dependent degradation domain by the HIF-P4Hs is required for binding of the von Hippel-Lindau E3 ubiquitin ligase complex (VHL) and for subsequent proteasomal degradation. Hydroxylation of a specific asparagine in the C-terminal transactivation domain by FIH blocks the binding of the transcriptional coactivator p300 (P300). Hypoxia inhibits the HIF-P4Hs and FIH, HIF-1α escapes degradation, forms a stable dimer with HIFβ, and binds p300. The active dimer binds to the HIF-responsive elements in a number of hypoxia-inducible genes and activates their transcription

Fig. 2

Hematoxylin and eosin staining of the proximal growth plate of mouse tibia at birth. ×10

Fig. 3

Histological section of the digital rays of an autopod of a mouse at embyonic day 13.5 (E13.5). Staining with the marker of hypoxia, EF5 (red), shows that the chondrocytes are hypoxic in the digital rays. The “interzones”, which will give rise to the perspective joints, are also highly hypoxic (white arrow). Bar 100 µm

Fig. 4

Histological sections of the distal epiphysis of newborn control (a) and Col2a1-Cre;HIF-1α^f/^f (b) mouse radiuses stained with hematoxylin and eosin. The mutant growth plate is severely misshapen, and its center is dramatically hypocellular as a consequence of massive central cell death. Bar 100 µm

Fig. 5

Histological sections of the digital ray of E13.5 control (a) and Prx1-Cre;HIF-1α^f/^f (b) mouse autopods stained with hematoxylin and eosin. Differentiated cuboidal chondrocytes are present in the control and undifferentiated mesenchymal cells in the mutant autopod. Bar 100 µm

Fig. 6

Model for HIF-1α-dependent regulation of early chondrocyte differentiation and survival