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Extracellular Matrix: The Driving Force of Mammalian Diseases

Authors and Affiliation

  • Renato V. Iozzo
    Department of Pathology, Anatomy, and Cell Biology and Cancer Cell Biology and Signaling Program, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
    Correspondence: renato.iozzo@jefferson.edu

  • Maria A. Gubbiotti

Abstract

  • The extracellular matrix (ECM) functions as a fundamental mediator for many intracellular events, much like the theme of a Mozart concerto.

  • Mechanisms of nearly all known diseases can be linked to abnormalities in the ECM, which affect downstream signaling axes and lead to cellular dysfunction, organ failure, and potentially death.

  • Major diseases driven by ECM include:

    • Connective tissue disorders

    • Muscular dystrophy

    • Fibrosis

    • Cancer

  • Understanding and modulating ECM-related mechanisms may lead to novel therapies.

Introduction

  • The human body consists of complex organ systems, each composed of various tissue types maintained by the ECM.

  • Definition of ECM: A compendium of signaling effectors that provides structural and functional support to surrounding cells; contains various proteins and signaling molecules:

    • Organizational proteins: Collagen, elastin

    • Hydrostatic regulators: Provides support and regulates cellular activities

    • Biochemically relevant signals: Proteoglycans, hyaluronan, etc.

  • The ECM's role is akin to a river sustaining an ecosystem. Lack of ECM can cause dysfunction, while an excess can lead to damage.

  • Early ECM studies focused on structural functions but have evolved towards understanding its regulatory capacity in both health and disease.

Importance of ECM in Disease

  • The ECM’s involvement spans various organ systems, from skin to internal organs, and plays critical roles in cancer and cellular dysregulation.

  • This study guide aims to present the importance of the ECM across multiple diseases in different organ systems.

ECM-Driven Connective Tissue Diseases

  • Start with matrix-related skin diseases, some of which are heritable and primarily arise from collagen abnormalities.

Examples of Skin Diseases

  1. Ehlers-Danlos Syndrome

    • Genetic disorder resulting from mutations in collagen or proteins regulating its organization (e.g., metalloproteinases).

    • Symptoms: Elastic skin, hyper-flexible joints, heart disease risks.

  2. Epidermolysis Bullosa (EB)

    • Characterized by fragile skin leading to blister formation; subtypes include:

      • Dystrophic EB: Collagen VII mutations affect dermal-epidermal anchoring.

      • EB Simplex: Keratin mutations leading to skin fragility.

      • Junctional EB: Mutations in laminin-332 and α6β4 integrin.

    • All subtypes expose patients to increased squamous cell carcinoma risk due to recurrent wound healing events.

Connective Tissue Disorders

  • Moving to bone and cartilage:

  1. Osteogenesis Imperfecta (OI)

    • Heritable disorder linked to collagen I mutations causing brittle bones, blue sclera, and short stature.

    • Severity and traits depend on mutation type; some can be lethal.

  2. Hereditary Multiple Exostoses (HME)

    • Caused by mutations affecting heparan sulfate biosynthesis.

    • Symptoms include multiple bony growths; management often surgical.

  3. Pseudochondroplasia

    • Autosomal dominant condition due to COMP defects, leading to growth and joint issues.

  4. Marfan Syndrome

    • Caused by fibrillin-1 mutations affecting elastic fibers, leading to tall stature and cardiovascular risks.

Muscular Dystrophies

  • Examples include congenital muscular dystrophy (CMD), Becker's muscular dystrophy (BMD), and Duchenne muscular dystrophy (DMD), associated with ECM connection failures and impairing muscle strength. Genetic factors often influence severity and presentation.

Age-Related Changes

  • Osteoarthritis and osteoporosis result from ECM turnover imbalances and can severely affect mobility and health, especially with aging.

Matrix Glitches in Internal Organ Systems

  • The ECM maintains organ homeostasis; improper signaling can disrupt function.

Fibrosis

  • An overproduction of connective tissue in various organs (e.g., pulmonary fibrosis, hepatic fibrosis) due to ECM dysregulation.

    • Pulmonary Fibrosis: Results in restrictive lung disease and can follow infections or occur idiopathically.

    • Hepatic Fibrosis: Activated stellate cells lead to scarring and eventual liver failure.

    • Renal Fibrosis: After injury or diabetes, fibrosis disrupts normal filtration functions, potentially resulting in end-stage renal disease.

A(vascular) Disaster: Effects on Vessels

  • Atherosclerosis and aneurysms result from ECM malfunctions affecting vessel integrity and formation.

Atherosclerosis

  • Characterized by lipid accumulation and abnormal ECM deposition in plaques, leading to cardiovascular events.

Aneurysms

  • Weakening of vessel walls, with the greatest risks posed by ruptures of aortic and cerebral aneurysms.

Cancer and the Malignant Matrix

  • The ECM contributes to tumor progression through altered signaling pathways, promoting neovascularization and metastasis.

  • Many ECM components interact with cancer cells to promote growth, with ongoing discovery in targeted therapies leveraging ECM interactions.

Conclusion

  • The role of the ECM in various diseases underscores the need for ongoing research into matrix biology.

  • Future research may unlock innovative therapies, aiming to mitigate the effects of ECM-related diseases.

Abbreviations

  • ADAMTS: A disintegrin and metalloproteinase with thrombospondin motifs

  • AGE: Advanced glycation end products

  • BM: Bethlem myopathy

  • BMD: Becker's muscular dystrophy

  • CMD: Congenital muscular dystrophy

  • COMP: Cartilage oligomeric matrix protein

  • DMD: Duchenne muscular dystrophy

  • EB: Epidermolysis bullosa

  • ECM: Extracellular matrix

  • EPHA2: Ephrin type-A receptor 2

  • ESRD: End-stage renal disease

  • EXT1/2: Exostosin-glycosyltransferase 1/2

  • FGF: Fibroblast growth factor

  • KRT: Keratin

  • MMP: Matrix metalloproteinase

  • OI: Osteogenesis imperfecta

  • ROS: Reactive oxygen species

  • RTK: Receptor tyrosine kinase

  • SLRP: Small, leucine-rich proteoglycan

  • TGF-β: Transforming growth factor beta

  • UCMD: Ulrich congenital muscular dystrophy

  • VEGF: Vascular endothelial growth factor

  • VEGFR2: Vascular endothelial growth factor receptor 2

Acknowledgements

  • Acknowledgment to scientists contributing to matrix biology and special thanks to past and present members of the Iozzo lab.

  • Funding from NIH grants CA39481 and CA47282.