An enzyme-proof glycan glue for extracellular matrix to ameliorate intervertebral disc degeneration

As the world’s population ages, intervertebral disc degeneration (IDD) has become a major medical issue, causing chronic lower back pain and mobility issues that diminish the quality of life for millions. The study from the University of Macau offers new hope with a novel “sugar glue” designed to repair damaged spinal discs. Led by Professor Chunming Wang, in collaboration with Professor Dong Lei of Nanjing University and supported by Professor Geng Dechun’s team at the First Affiliated Hospital of Soochow University. The research introduces a glucomannan-based solution that restores disc health by targeting a key protein, published in Nature Communications, titled “An enzyme-proof glycan glue for extracellular matrix to ameliorate intervertebral disc degeneration.”  (https://rdcu.be/ejPlG).

The research team screened the Human Musculoskeletal System gene expression database (MSdb) from Zhejiang University and clinical samples, and they discovered significant variations in Milk Fat Globule-Epidermal Growth Factor 8 (MFG-E8) expression levels during IDD. Therefore, the team considered MFG-E8 as a protein critical for maintaining disc integrity. MFG-E8 is a secreted glycoprotein with an N-terminal Epidermal Growth Factor (EGF)-like domain binding to integrin receptors with an RGD motif and a C-terminal F5/8-type domain interacting with phospholipids and glycans. This distinctive structure enables MFG-E8 to function as a molecular bridge, mediating cell-cell and cell-matrix interactions, promoting cell adhesion, remodelling the extracellular matrix (ECM), and balancing the overall tissue microenvironment. This finding indicates that the loss of MFG-E8 disrupts the disc’s microenvironment, accelerating degeneration.

In this context, the team synthesised a glucomannan ester, GMOC, with a structure mimicking natural GAGS and exceptional resistance to enzymatic degradation. GMOC actively enhances endogenous MFG-E8 in the degenerative microenvironment, regulating nucleus pulposus cell function and slowing the progression of IDD. In healthy nucleus pulposus tissue, abundant glycosaminoglycans (GAGS), such as hyaluronic acid and chondroitin sulfate, maintain tissue integrity. Hyaluronic acid (HA) is often known as a filler to improve the degenerative microenvironment, but it is rapidly degraded by increased hyaluronidase-2 (HYAL-2) in IDD. Unlike hyaluronic acid, GMOC resists enzymatic degradation, remaining stable at the implantation site. Experiments confirmed GMOC’s highest affinity for MFG-E8 compared to other glucomannan derivatives. Atomic force microscopy (AFM) and cellular thermal shift assay (CETSA) further demonstrated that GMOC mimics natural GAGs-MFG-E8 interactions, forming complexes with similar morphology.

The team validated these findings in rat and rabbit models simulating different clinical scenarios. In a rat IDD model, GMOC injections alleviated early-stage degeneration by enhancing tissue hydration, maintaining disc height, and preserving tissue integrity over four weeks, while also improving mechanical stability and alleviating pain. Meanwhile, to address post-surgical repair challenges and prevent recurrence, a rabbit model of partial disc resection, where GMOC filling effectively maintained tissue integrity over six weeks.

Despite these achievements, the team noted a limitation: the challenge of using MFG-E8 knockout rat models to further clarify its regulatory mechanisms, as the rat Mfge8 gene coding region overlaps with the Hapln3 gene coding region, affecting hyaluronic acid synthesis and complicating mechanistic studies. The team hopes to collaborate with global researchers to develop such models and further explore MFG-E8’s role in tissue repair.

This study was financially supported by the Science and Technology Development Fund, Macao SAR, the National Science Foundation of China, Jiangsu Provincial Science and Technology Plan Special Fund, and the University of Macau.

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