# Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $462,548

## Abstract

The relationship between the etiology of intervertebral disc degeneration and low back pain has been subjected
to considerable scrutiny. Degeneration is thought to be initiated by the abnormal production of a number of
pro-inflammatory cytokines, in particular TNF-α and IL-1β. While these studies have shown involvement of
cytokines in pathogenesis of disc degeneration and herniation, progress has been slow in delineating new
therapeutic targets to block inflammation. This deficit stems from our lack of understanding of molecular
mediators that regulate and link cytokine-dependent matrix degradation with immune cell migration into the
disc through annular defects. Interestingly, our ongoing work has found an unexpected synergism between
heparan sulfate (HS) proteoglycan syndecan4 (SDC4) and these two key inflammatory cytokines. The goal of
the proposed investigations is to build on the central role of SDC4 in the pathogenesis of the disc herniation
and inflammation. We have formulated two interrelated hypotheses each of which addresses a separate but
linked phase of the disease process. The first phase relates to the effect of the inflammatory cytokines on the
regulation of aggrecan rich matrix degradation. We will test the hypothesis that SDC4 through HS side chains
promotes cytokine-dependent aggrecan rich matrix degradation through ADAMTS and MMP activation. Using
gain and loss-of-function studies of SDC4 in NP cells treated with cytokines and RNA-Seq approach we will
identify novel SDC4 responsive genes. We will also measure the contribution of MMPs, ADAMTS-1 and
ADAM17 produced by NP cells in SDC4 shedding. In addition, we will determine how changes in SDC4 levels
relate to aggrecan and collagen turnover in human tissues. The second stage of the disease process is
characterized by structural changes in the NP and AF and formation of annular tears and herniations. We
propose to test the hypothesis that that in inflammatory milieu of the herniated disc, SDC4 plays an important
role in macrophage activation and migration by controlling the activity of select chemokines (CCL5, IL-8 and
SDF-1) secreted by the disc cells. This will be achieved using primary macrophages isolated from SDC4-/- mice.
Using well characterized painful human disc tissues, we will link changes in chemokines and SDC4 levels to
immune cell activation, infiltration and matrix degradation. Finally, to explore the in vivo importance of SDC4
in pathogenesis of TNF--driven disc herniation, we will cross hTNFtg mice with SDC4 -/- animals to generate
hTNFtg,SDC4-/- mice. To establish if a deficiency in SDC4 provides protection against cytokine-dependent disc
herniation, we will compare molecular, structural and biomechanical properties of the motion segments with
that of hTNFtg. To our knowledge, this would be the first attempt to address the contribution of SDC4 to
mechanisms linking initiation and propagation of the degenerative cascade and herniation driven by
inflammatory cyto...

## Key facts

- **NIH application ID:** 9895623
- **Project number:** 5R01AR074813-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Makarand V Risbud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,548
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895623

## Citation

> US National Institutes of Health, RePORTER application 9895623, Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4 (5R01AR074813-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895623. Licensed CC0.

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