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. 2020 Apr 21:6-7:100036.
doi: 10.1016/j.mbplus.2020.100036. eCollection 2020 May.

Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration

Takashi Ohnishi  1   2 , Emanuel J Novais  1   3   4 , Makarand V Risbud  1
Affiliations

Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration

Takashi Ohnishi et al. Matrix Biol Plus. .

Abstract

The intervertebral disc is a specialized connective tissue critical for absorption of mechanical loads and providing flexibility to the spinal column. The disc ECM is complex and plays a vital role in imparting tissue its biomechanical function. The central NP is primarily composed of large aggregating proteoglycans (PGs) while surrounding AF is composed of fibrillar collagens, I and II. Aggrecan and versican in particular, due to their high concentration of sulfated GAG chains form large aggregates with hyaluronic acid (HA) and provide water binding capacity to the disc. Degradation of aggrecan core protein due to aggrecanase and MMP activity, SNPs that affect number of chondroitin sulfate (CS) substitutions and alteration in enzymes critical in synthesis of CS chains can impair the aggrecan functionality. Similarly, levels of many matrix and matrix-related molecules e.g. Col2, Col9, HAS2, ccn2 are dysregulated during disc degeneration and genetic animal models have helped establish causative link between their expression and disc health. In the degenerating and herniated discs, increased levels of inflammatory cytokines such as TNF-α, IL-1β and IL-6 are shown to promote matrix degradation through regulating expression and activity of critical proteases and stimulate immune cell activation. Recent studies of different mouse strains have better elucidated the broader impact of spontaneous degeneration on disc matrix homeostasis. SM/J mice showed an increased cell apoptosis, loss of cell phenotype, and cleavage of aggrecan during early stages followed by tissue fibrosis evident by enrichment of several collagens, SLRPs and fibronectin. In summary, while disc degeneration encompasses wide spectrum of degenerative phenotypes extensive matrix degradation and remodeling underscores all of them.

Keywords: Annulus fibrosus; Disc degeneration; Extracellular matrix; Fibrosis; Intervertebral disc; Nucleus pulposus; Sub-phenotypes.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
A scheme of important signaling pathways and matrix molecules that play roles in intervertebral disc health and disease. Notochordal cells (NCs) populate in the center of the nucleus pulposus (NP) and communicate with each other by many gap junctions (GJs). The annulus fibrosus (AF) and cartilaginous endplate (CEP) encapsulate the NP.
Fig. 2
Fig. 2
Phenotypic differences observed between SM/J and LG/J mice, mainly focusing on molecular regulation and composition of the intervertebral disc (Ref #9, 10). SM/J mice evidence spontaneous early onset disc degeneration characterized by extensive cellular and matrix changes.
Fig. 3
Fig. 3
Predominant disc degeneration phenotypes and their ECM signatures. Each degenerative sub-type is characterized by a unique extracellular matrix composition and remodeling signature. Red (increase) and blue (down) arrows represent directionality of the change respectively. Abbreviations: collagen (COL); proteoglycans (PGs); tissue non-specific alkaline phosphatase (TNAP); metalloproteases (MMP); A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS); aggrecan (ACAN); progranulin (PGRN); ATP-binding cassette sub-family C member 6 (ABCC6); aggrecanase (ADAMTS-1, -4 & -5)-generated N-terminal neoepitope ARG after cleavage (ARGxx); Nucleus pulposus (NP); Annulus fibrosis (AF).
See this image and copyright information in PMC

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