Enzyme-resistant glycan glue ameliorates spinal disk degeneration in animal models

As the world’s population ages, intervertebral disk 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 disks.

The research was 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 disk health by targeting a key protein. The paper, titled “An enzyme-proof glycan glue for extracellular matrix to ameliorate intervertebral disk degeneration,” is published in Nature Communications,

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 disk 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, remodeling the extracellular matrix (ECM), and balancing the overall tissue microenvironment.

This finding indicates that the loss of MFG-E8 disrupts the disk’s microenvironment, accelerating degeneration.

In this context, the team synthesized 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 disk 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 disk 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.

Provided by
Nanjing University School of Life Sciences

As the world’s population ages, intervertebral disk 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 disks.

The research was 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 disk health by targeting a key protein. The paper, titled “An enzyme-proof glycan glue for extracellular matrix to ameliorate intervertebral disk degeneration,” is published in Nature Communications,

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 disk 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, remodeling the extracellular matrix (ECM), and balancing the overall tissue microenvironment.

This finding indicates that the loss of MFG-E8 disrupts the disk’s microenvironment, accelerating degeneration.

In this context, the team synthesized 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 disk 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 disk 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.

Provided by
Nanjing University School of Life Sciences