CTGF/CCN2 from Skeletal Muscle to Nervous System: Impact on Neurodegenerative Diseases

Abstract

Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that belongs to the CCN family of proteins. Since its discovery, it has been linked to cellular processes such as cell proliferation, differentiation, adhesion, migration, and synthesis of extracellular matrix (ECM) components, among others. The pro-fibrotic role of CTGF/CCN2 has been well-studied in several pathologies characterized by the development of fibrosis. Reduction of CTGF/CCN2 levels in mdx mice, a murine model for Duchenne muscular dystrophy (DMD), decreases fibrosis and improves skeletal muscle phenotype and function. Recently, it has been shown that skeletal muscle of symptomatic hSOD1G93A mice, a model for Amyotrophic lateral sclerosis (ALS), shows up-regulation of CTGF/CCN2 accompanied by excessive deposition ECM molecules. Elevated levels of CTGF/CCN2 in spinal cord from ALS patients have been previously reported. However, there is no evidence regarding the role of CTGF/CCN2 in neurodegenerative diseases such as ALS, in which alterations in skeletal muscle seem to be the consequence of early pathological denervation. In this regard, the emerging evidence shows that CTGF/CCN2 also exerts non-fibrotic roles in the central nervous system (CNS), specifically impairing oligodendrocyte maturation and regeneration, and inhibiting axon myelination. Despite these striking observations, there is no evidence showing the role of CTGF/CCN2 in peripheral nerves. Therefore, even though more studies are needed to elucidate its precise role, CTGF/CCN2 is starting to emerge as a novel therapeutic target for the treatment of neurodegenerative diseases where demyelination and axonal degeneration occurs.

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Fig. 1

Abbreviations

ALS:

Amyotrophic lateral sclerosis

CNS:

Central nervous system

CTGF/CCN2:

Connective tissue growth factor

DMD:

Duchenne muscular dystrophy

ECM:

Extracellular matrix

PNS:

Peripheral nervous system

TGF-β:

Transforming growth factor type β

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Funding

This work was supported by CONICYT AFB170005 and FONDECYT 1150106 to E.B., and Beca de Doctorado Nacional from CONICYT to D.G. The funding agencies had no role in the design of the study, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Enrique Brandan.

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Gonzalez, D., Brandan, E. CTGF/CCN2 from Skeletal Muscle to Nervous System: Impact on Neurodegenerative Diseases. Mol Neurobiol 56, 5911–5916 (2019). https://doi.org/10.1007/s12035-019-1490-9

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Keywords

  • CTGF/CCN2
  • Skeletal muscle
  • Central nervous system
  • Peripheral nerves
  • Myelination
  • Fibrosis