Fibrotic-like changes in degenerate human intervertebral discs revealed by quantitative proteomic analysis

Yee, Anita; Lam, M. P. Y.; Tam, Vivian; Chan, Wing‐Lok; Chu, IK; Cheah, Kathryn S.E.; Cheung, Kenneth M.C.; Chan, Danny

doi:10.1016/j.joca.2015.09.020

Cited by 61 publications

(102 citation statements)

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“…In Pathway analysis (Fig.2B-C), both data showed significant enrichment in ECM interaction, Focal adhesion and PI3K-Akt signaling pathways. However, only protein data showed significant enrichment in TGF-beta signaling pathway and HIF-1 signaling pathway ( Supplementary Dataset 4), which is concordant with previous reports (2,16,17). These findings showed that the changes of either transcriptome and proteome of the degenerated NP cells is indeed related to the extracellular matrix remodeling or degeneration, but there also exist great differences in the enriched gene functions and pathways of the differentially expressed genes between mRNA and protein data.…”

Section: Functional Analysis Of Differentially Expressed Genessupporting

confidence: 90%

Integrated transcriptome and proteome analyses identifies novel genes and regulatory networks in intervertebral disc degeneration

Luo

Wei

et al. 2019

Preprint

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Background: Intervertebral disc degeneration is a major cause of symptoms like low back pain and neck pain. Many groups have tried to reveal the regulatory network using either transcriptome or proteome profiling technologies, however, the relationship between these differentially expressed proteins and mRNAs are not elucidated. Since post-transcriptional regulation and other mechanisms may affect the translation of mRNA to protein, a combined transcriptome and proteome study may give more precise data on unveiling important regulatory network and key genes of Intervertebral disc degeneration. Results: In the present study, we used the label-free quantification proteomic approach and identify 656 proteins expressed in either degenerated or normal nucleus pulposus, of which 503 proteins are differentially expressed. Taking advantage of the existing nucleus pulposus transcriptome data, we combine and reanalyze the data and find 105 differentially expressed mRNA between degenerated and normal nucleus pulposus. By comparing these data, only 9 genes show significant changes in both protein and mRNA data, while 6 genes (TNFAIP6, CHI3L1, KRT19, DPT, COL6A2 and COL11A2) show concordant changes in both protein and mRNA level. Further functional analyses show different functions of the altered mRNAs and proteins in degeneration, indicating great difference between protein network and mRNA network. Using the gene co-expression network method, we uncover novel regulatory network and potential genes that may play vital roles in intervertebral disc degeneration by combining protein and mRNA data. Conclusions: This is the first study to identify novel regulatory network of intervertebral disc degeneration using combined analysis of both transcriptome and proteome, which may give new insight into the molecular mechanism of intervertebral disc degeneration.

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Section: Functional Analysis Of Differentially Expressed Genessupporting

confidence: 90%

Integrated transcriptome and proteome analyses identifies novel genes and regulatory networks in intervertebral disc degeneration

Luo

Wei

et al. 2019

Preprint

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“…However, in both conditional mutant mice we did observe a consistent upregulation of several fibrillar type collagens, including Col1a1, Col3a1 among others at P20 in Col2Cre;Adgrg6 f/f mutant mice ( Figure 4E) and Col1a1 and Col3a1in ATC;Adgrg6 f/f mutant mice at 1.5 months ( Figure 2O). Similar shifts from non-fibrous, predominantly type II collagens to fibrillar collagens, such as type I, are common signals reported in studies of degenerative IVD from both human and mouse models (Antoniou et al, 1996;Chen et al, 2016;Yee et al, 2016;Zhang et al, 2018). We suggest that the increased expression of more fibrotic extracellular matrix genes may underlie increased stiffness of the IVD we observed in ATC;Adgrg6 f/f mutant mice ( Figure 3) and contribute to susceptibility of endplate-oriented disc herniations during aging in these mutant mice (Figure 1).…”

Section: Loss Of Adgrg6 In the Intervertebral Disc Leads To Increasessupporting

confidence: 64%

Homeostasis of the intervertebral disc requires regulation of STAT3 signaling by the adhesion G-protein coupled receptor ADGRG6

Liu

Easson²,

Jin

et al. 2019

Preprint

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Degenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide. While this is primarily attributed to trauma and aging, genetic variation is associated with disc degeneration in humans. However, the precise mechanisms driving the initiation and progression of disease remain elusive due to a paucity of genetic animal models.Here, we discuss a novel genetic mouse model of endplate-oriented disc degeneration. We show that the adhesion G-protein coupled receptor G6 (ADGRG6) mediates several anabolic and catabolic factors, fibrotic collagen genes, pro-inflammatory pathways, and mechanical properties of the IVD, prior to the onset of overt histopathology of these tissues. Furthermore, we found increased IL-6/STAT3 activation in the IVD and demonstrate that treatment with a chemical inhibitor of STAT3 activation ameliorates disc degeneration in these mutant mice. These findings establish ADGRG6 as a critical regulator of homeostasis of adult disc homeostasis and implicate ADGRG6 and STAT3 as promising therapeutic targets for degenerative joint diseases. Author summaryDegenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide. While this is primarily attributed to trauma and aging, genetic variation is associated with disc degeneration in humans. However, the precise mechanisms driving the initiation and progression of disease remain elusive due to a paucity of genetic animal models.Here, we discuss a novel genetic mouse model of endplate-oriented disc degeneration. We show that the adhesion G-protein coupled receptor G6 (ADGRG6) mediates fibrotic collagen expression, causing increased mechanical stiffness of the IVD prior to the onset of histopathology in adult mice. Furthermore, we found increased IL-6/STAT3 activation in the IVD and demonstrate that treatment with a chemical inhibitor of STAT3 activation ameliorates disc degeneration in these mutant mice. Our results demonstrate that ADGRG6 regulation of STAT3 signaling is important for IVD homeostasis, indicating potential therapeutic targets for degenerative joint disorders.

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“…Back pain is most frequently the result of impingement of local nerves by herniation or bony structures resulted from the degenerated disc. Anatomical studies of autopsies and surgical specimens show evidence of fibrosis in the majority of degenerated discs [9-12]. Fibrosis is common under chronic inflammatory conditions and is associated with excessive tissue remodeling and abnormal collagen matrix deposition [13-19].…”

Section: Introductionmentioning

confidence: 99%

Injectable nanofibrous spongy microspheres for NR4A1 plasmid DNA transfection to reverse fibrotic degeneration and support disc regeneration

et al. 2017

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Safe and efficient gene therapy is highly desired for controlling pathogenic fibrosis of nucleus pulposus (NP) tissue, which would result in intervertebral disc (IVD) degeneration and disability if left untreated. In this work, a hyperbranched polymer (HP) with high plasmid DNA (pDNA) binding affinity and negligible cytotoxicity is synthesized, which can self-assemble into nano-sized polyplexes with a “double shell” structure that can highly efficiently transfect pDNA into NP cells. These polyplexes are then encapsulated in biodegradable nanospheres (NS) to enable two-stage delivery: 1) temporally-controlled release of pDNA-carrying polyplexes and 2) highly efficient delivery of pDNA into cells by the released polyplexes. These biodegradable NS are co-injected with nanofibrous spongy microspheres (NF-SMS) to localize the cellular transfection of the pDNA encoding orphan nuclear receptor 4A1 (NR4A1), which was recently reported as a therapeutic agent to delay pathogenic fibrosis. It is shown that HP can transfect human NP cells efficiently in vitro with low cytotoxicity. The two-stage delivery system is able to present the polyplexes over a sustained time period (more than 30 days) in the tail of rat. The NR4A1 pDNA carried by the HP polyplexes is found to therapeutically reduce the pathogenic fibrosis of NP tissue in a rat-tail degeneration model. In conclusion, the combination of the two-stage NR4A1 pDNA delivery NS and NF-SMS is able to repress fibrosis and to support IVD regeneration.

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Fibrotic-like changes in degenerate human intervertebral discs revealed by quantitative proteomic analysis

Abstract: Our study identified distinct matrix changes associated with aging and degeneration in the intervertebral discs (IVDs). The nature of the ECM changes, together with observed decreased in solubility and changes in fibril diameter is consistent with a fibrotic-like environment.

Cited by 61 publications

References 50 publications

Integrated transcriptome and proteome analyses identifies novel genes and regulatory networks in intervertebral disc degeneration

Integrated transcriptome and proteome analyses identifies novel genes and regulatory networks in intervertebral disc degeneration

Homeostasis of the intervertebral disc requires regulation of STAT3 signaling by the adhesion G-protein coupled receptor ADGRG6

Injectable nanofibrous spongy microspheres for NR4A1 plasmid DNA transfection to reverse fibrotic degeneration and support disc regeneration

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