Matrisome Profiling During Intervertebral Disc Development And Ageing (original) (raw)

Intervertebral disc (IVD) degeneration is often the cause of low back pain. Degeneration occurs with age and is accompanied by extracellular matrix (ECM) depletion, culminating in nucleus pulpous (NP) extrusion and IVD destruction. The changes that occur in the disc with age have been under investigation. However, a thorough study of ECM profiling is needed, to better understand IVD development and age-associated degeneration. As so, iTRAQ LC-MS/MS analysis of foetus, young and old bovine NPs, was performed to define the NP matrisome. The enrichment of Collagen XII and XIV in foetus, Fibronectin and Prolargin in elder NPs and Collagen XI in young ones was independently validated. This study provides the first matrisome database of healthy discs during development and ageing, which is key to determine the pathways and processes that maintain disc homeostasis. The factors identified may help to explain age-associated IVD degeneration or constitute putative effectors for disc regeneration. The intervertebral disc (IVD) is a complex structure capable of resisting spinal compression while allowing motion of intervertebral segments 1, 2. Besides water, it is mainly composed by extracellular matrix (ECM) molecules. These include collagens, proteoglycans (PGs) and other matrix proteins that contribute to the structural and mechanical function of the disc 3, 4. Matrix degrading enzymes are also present to regulate matrix breakdown, maintaining disc homeostasis 5. A young healthy disc consists of a highly plastic and hydrated region-the nucleus pulposus (NP)-and a network of collagen fibres oriented in sheets around the nucleus-the annulus fibrosus (AF), which provides tensile strength and confines the NP, limiting bulging 6. During disc degeneration and ageing, significant changes are observed in the IVD at both cell and tissue level. From birth, notochordal cells gradually disappear from the NP 7. Loss of cell density is accompanied by a shift towards a chondrocyte-like cell population 3 , less effective in NP-specific matrix synthesis 8. Ultimately this results in NP fibrous transformation, from a translucent gel to a more solid and cartilaginous tissue 1 making it difficult to distinguish between NP and AF 6. Alterations in the composition and mechanical properties of the surrounding environment will in turn influence NP cell function and behaviour, in terms of differentiation, metabolism, proliferation and survival 8. Along with cellular changes, NP matrix remodeling is also an early step in the ageing process. Apart from overall matrix breakdown caused by MMPs (matrix metalloproteinases) and ADAMTS (a desintegrin and metalloprotease with thrombospondin motifs) overexpression 7 , PG and collagen synthesis patterns 9, 10 , as well as fibre crosslinking 1 are also altered. This inhibits matrix turnover and, together with the already limited repair response, leads to dehydration and progressive ECM disorganization. Furthermore, it promotes mechanical failure, annular tears and many of the characteristic features of disc degeneration 6. Over time, type II collagen is replaced by