Identification of Biomarkers and Molecular Targets Involved on Intervertebral Disc Degeneration and Discogenic Pain

Overview

Low back pain, associated with intrinsic disorders of the spine, is a very frequent clinical condition that is accompanied by high morbidity with effects both on psychosocial aspects, and health care system. It occurs in approximately 80% of the population throughout their lives. Most low back pain is associated with intervertebral disc degeneration (IDD) associated with neuroinflammation and pain. In this context, the study of sphingolipid metabolism can play an important role in the identification of new molecules responsible for the degenerative process. Sphingolipids, in fact, are a class of molecules that are implicated in multiple signal pathways, such as proliferation, degradation of the extracellular matrix, inflammatory state, apoptosis and migration. In particular, sphingosine-1-phosphate (S1P), an intermediate of sphingolipid metabolism, acts as a pro-inflammatory mediator, predominantly in the extracellular environment, regulating important cellular properties related to inflammatory potential and pain. The objective of this study is to characterize the degenerative process in cells isolated from degenerated human intervertebral discs from both at cellular and molecular levels in order to identify new targets implicated in degenerative processes, including sphingolipid signaling pathway.

Low back pain (LBP) is a serious public health problem and has been identified as the most widespread cause of disability worldwide by the 2013 Global Burden of Disease Study. It is estimated that in the Western world the annual incidence of acute low back pain is 5% in adults and that the lifetime prevalence is 80%. Although different anatomical structures can be implicated in the generation of LBP, in many cases this is associated with the degeneration of the intervertebral disc (IVD). IVD degeneration (IDD) represents a chronic age-related process, characterized by a progressive reduction in the content of proteoglycans and water in the nucleus pulposus (NP) with the subsequent loss of the ability of the disc to respond to compressive forces with the possible appearance of instability. Furthermore, this degenerative process is accompanied by the development of a highly inflammatory microenvironment which contributes to exacerbating the degenerative process, leading to the progressive structural failure of the disc itself and in most cases, to pain. From these premises, arises the need to better investigate all the cell-mediated mechanisms underlying IDD, to identify and develop new therapies aimed at recovering the IVD and reducing pain. In this context, sphingolipids, a class of molecules responsible for multiple signal pathways such as proliferation, migration, apoptosis and angiogenesis, appear to play a key role in exacerbating the inflammatory process and degradation of the extracellular matrix in conditions of IDD. Sphingosine-1-phosphate (S1P) is an intermediate of sphingolipid metabolism, formed from sphingosine through the action of sphingosine kinases (SphK1, SphK2). Increasing evidence suggests that S1P acts as a pro-inflammatory signal, predominantly in the extracellular environment, regulating important cellular properties correlated with the inflammatory potential on chondrocyte-like cells. It has been reported that an alteration in the production and secretion of these molecules is capable of increasing the inflammatory and degenerative condition in various pathologies related to neuroinflammation and pain. The aim of the project is to define new disease biomarkers and characterize the degenerative process in cells isolated from degenerated human intervertebral discs from both at cellular and molecular levels in order to identify new targets implicated in degenerative processes, including sphingolipid signaling pathway. Secondary objective is the analysis of the effectiveness of the modulation of sphingolipid metabolism and the in vitro testing of molecules with therapeutic potential. A greater understanding of the events implicated in the pathogenesis of IDD both at macroscopic and microscopic levels, is of fundamental importance for the development of new diagnostic tools, to be combined with current therapeutic strategies.