Natriuretic peptide signalling in intervertebral disc degeneration

Lower back pain (LBP) is responsible for a third of all work-related disability. Degeneration of intervertebral discs (IVDs) is responsible for 40% of LBP cases, making it a significant health burden, however its pathogenesis is poorly understood. The degeneration is associated with expression of proinflammatory cytokines1, and IVDs show age-related changes earlier than any other connective tissue in the body.

Natriuretic peptides have beneficial effects on the health of musculoskeletal tissues, and in particular, C-natriuretic peptide (CNP) stimulates extracellular matrix repair and dampens the effects of inflammation by antagonising pro-inflammatory cytokine function2, making it an important mediator of tissue repair in musculoskeletal diseases.

To date, there are no studies of natriuretic peptide signalling in the IVD, or the link between CNP, matrix breakdown or other catabolic events during IVD degeneration. CNP targets two receptors, which have distinct downstream functional effects. The balance between these two receptors is altered by age, disease and inflammatory environment, making them potential therapeutic targets to reduce the impact of IVD degeneration.

This project will investigate natriuretic peptide signalling as a potential therapeutic avenue in degenerate disc disease, to dampen inflammation and promote tissue repair. Initial studies will assess the components of the natriuretic peptide signalling pathways in non-degenerate and degenerate human discs using immunohistochemistry and qPCR, and analyse the response of nucleus pulposas cell cultures to CNP, as well as agonists and antagonists of the natriuretic peptide pathway.

The objective will be to identify whether agents targeting natriuretic peptide signalling can inhibit catabolic events and promote repair of degenerate discs, and to establish a therapeutic rationale for this debilitating condition.

Experimental aims:

1. Examine CNP and natriuretic peptide receptor expression in tissue from non-degenerate and degenerate human IVDs.

2. Analyse the response of nucleus pulposus (NP) cells cultured in alginate to CNP, and to agonists and antagonists of CNP signalling.

3. Determine the ability of CNP and the natural receptor antagonist osteocrin to inhibit IL-1β regulated catabolic events in human NP cells in alginate culture.

4. Develop a rationale for CNP-based therapeutics for the treatment of degenerative disc disease.

Dr Le Maitre has established a bank of IVD tissues at SHU which will be used to measure mRNA and protein levels of CNP, osteocrin and the natriuretic peptide receptors Npr-2 and -3. These tissues span across a range of disease stages, and patient ages. Protocols are also established for the isolation and culture of NP cells for the analysis of the effects of CNP. Candidates should have some experience of cell culture, and a background incorporating histological and musculoskeletal elements would be an advantage, but training in all techniques will be provided by the supervisory team, whom together have extensive experience in the techniques required for the successful completion of this programme of work.