Hypoxia and intervertebral disc pathologies

Affecting 80 % of the general population, low back pain represents one of the major socioeconomic burdens in industrialised countries. The underlying IVD degeneration and a progressive disappearance of the nucleus pulposus (NP) structure are the subjects of active research. Within the IVD, the progenitor cells are exposed to low oxygen, or hypoxia. Adaptation to hypoxia is a critical developmental event, controlled by a variety of cellular functions.

The ongoing EU-funded DISKOMICE (Diskomice) project is investigating the role of hypoxia-inducible factors (HIFs) in the development of IVD and cartilaginous growth plate. This four-year study is dedicated to the molecular mechanisms of proliferation, survival and differentiation of NP cells during developmental and degenerative processes. Scientists developed genetically modified mice to specifically inactivate HIF genes during embryonic development, growth and ageing.

DISKOMICE demonstrated that von Hippel-Lindau protein is a critical regulator of bone morphogenesis. The loss of this enzyme, normally targeting HIFs to the proteasome for degradation, considerably altered size, shape and overall development of the skeletal elements. It caused the structural collapse of the cartilaginous growth plate as a result of impaired proliferation. The resulting phenotype was associated with a delayed replacement of cartilage by bone.

The loss of HIF-1 caused the progressive disappearance and replacement of the NP with a novel tissue resembling fibrocartilage. Mutant NP cells underwent massive cell death and were completely replaced by a different cell lineage. Biomechanical testing of mutant IVD allowed evaluation of the functional consequences of HIF-1 deletion in the NP. It showed that the loss of the NP in mutant mice significantly reduced the IVD biomechanical properties by decreasing its ability to absorb mechanical stress. These findings are similar to the changes usually observed during human IVD degeneration.

Mouse models developed by DISKOMICE provide better understanding of the hypoxic signalling pathway in cartilage and IVD tissues and will help define novel therapeutic molecular targets.