Syndecan-4 in intervertebral disc and cartilage: Saint or synner?

Abstract

The ECM of the intervertebral disc and articular cartilage contains a highly organised network of collagens and proteoglycans which resist compressive forces applied to these tissues. A pathological hallmark of the intervertebral disc is the imbalance between production of anabolic and catabolic factors by the resident cells. This process is thought to be mediated by pro-inflammatory cytokines, predominantly TNF-α and IL-1β, which upregulate expression of matrix degrading enzymes such as MMPs and ADAMTSs. This imbalance ultimately results in tissue degeneration causing failure of the biomechanical function of the tissues. A similar cascade of events is thought to occur in articular cartilage during development of osteoarthritis. Within these skeletal tissues a small, cell surface heparan sulphate proteoglycan; syndecan-4 (SDC4) has been implicated in maintaining physiological functions. However in the degenerating niche of the intervertebral disc and cartilage, dysregulated activities of this molecule may exacerbate pathological changes. Studies in recent years have elucidated a role for SDC4 in mediating matrix degradation in both intervertebral discs and cartilage by controlling ADAMTS-5 function and MMP3 expression. Discourse presented in this review highlights the potential of SDC4 as a possible therapeutic target in slowing the progression of ECM degradation in both degenerative disc disease and osteoarthritis.

Keywords: Cartilage; Cytokines; Disc degeneration; Extracellular matrix; Intervertebral disc; Syndecan-4.

Figure 1

(A) Schematic representation of the IVD. (B, C) Immunofluorescent staining of SDC4 in murine IVD shows strong localization in nucleus pulposus (B) and inner two thirds of the annulus fibrosus (C). Scale bars; 200 μm. NP, nucleus pulposus; AF, annulus fibrosus; CEP, cartilaginous endplate.

Figure 2. The core-domain structure of syndecans

The extracellular domain is depicted in red and both heparan and chondroitin sulphate chains are indicated by the blue lines. Cleavage sites are indicated by purple blocks, followed by a short transmembrane domain in blue. Each syndecan has a short cytoplasmic domain in which a variable region is flanked by two highly conserved regions termed C1 and C2. Cleavage of the ectodomain can occur via numerous metalloproteinases such as MMP2, 3, 7 and 9, as well as proteases thrombin and plasmin. HS, Heparan sulphate; CS, Chondroitin sulphate; SDC, syndecan; TM, transmembrane.

Figure 3. The role of SDC4 in the degenerating nucleus pulposus

In the degenerating NP, the increase in inflammatory cytokines TNF-α and IL-1β drives the expression of catabolic enzymes MMP-3 and ADAMTS-5, and have also been shown to regulate SDC4 expression via MAPK and NF-κB signalling pathways. SDC4 selectively interacts with ADAMTS-5 at the cell surface promoting its activation and subsequent cleavage of aggrecan. SDC4 is also important in controlling TNF-dependent MMP-3 expression via MAPK and NF-κB pathways. The expression of these catabolic factors leads to the degeneration of the IVD. Likewise, IL-1β induced SDC4 is supressed by CCN2/CTGF bound to integrins αvβ3 and α5β1. Additionally, anabolic growth factor TGFβ inhibits NF-κB signalling in NP cells, supressing SDC4 and MMP-3 expression.