Extracellular Matrix Proteins in Connective Tissue Disorders

The extracellular matrix (ECM) provides structural and biochemical support to cells, with a complex network of proteins such as fibrillins, elastins, fibulins and microfibril‐associated glycoproteins. Inherited or acquired alterations of these ECM components underlie a spectrum of connective tissue disorders, from Marfan syndrome and Weill–Marchesani syndrome to various forms of skeletal dysplasia and vascular aneurysms. Mutations in fibrillin‐1 disrupt the assembly and elasticity of microfibrils, leading to aberrant growth factor sequestration and dysregulated TGF-β signalling. Elastin and its precursor tropoelastin ensure tissue resilience, while accessory glycoproteins like MFAP4 and fibulins modulate fibre assembly and stability. The interplay between ECM architecture and growth factor bioavailability shapes tissue homeostasis, and defects in these interactions manifest as musculoskeletal, cardiovascular and pulmonary pathologies. Recent advances in high‐resolution structural biology and mechanistic studies are refining our understanding of how specific molecular alterations provoke disease, guiding the development of targeted therapeutic strategies.

Research from Nature Portfolio

Recent studies have elucidated the atomic architecture and assembly dynamics of key ECM glycoproteins. A cryogenic electron microscopy analysis of microfibril‐associated glycoprotein 4 (MFAP4) revealed that in the presence of calcium, MFAP4 forms octameric assemblies linked by disulphide bonds and salt bridges. These octamers interact with fibrillin‐1, tropoelastin and integrin receptors, identifying multiple binding surfaces essential for elastic fibre organisation and cellular adhesion. This work offers a structural basis for MFAP4’s roles in organ fibrosis and vascular disorders. Concurrently, high‐resolution structures of native fibrillin microfibrils unveiled an eightfold pseudo‐symmetry at the bead region, localising the latent TGF-β‐binding protein interaction site. Pathogenic deletions within this region provoke long‐range conformational changes, abrogating growth factor sequestration and promoting dysregulated signalling associated with Marfan and related syndromes.

Extracellular Matrix Proteins in Connective Tissue Disorders publication trend

The graph below shows the total number of articles in extracellular matrix proteins in connective tissue disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Extracellular matrix (ECM): A structural network of proteins and polysaccharides surrounding cells, providing mechanical support and biochemical cues.

Microfibril: A filamentous ECM assembly composed primarily of fibrillin that provides elasticity and growth factor sequestration.

Fibrillin: A large glycoprotein that polymerises into microfibrils and regulates TGF-β/BMP availability.

Tropoelastin: The soluble precursor of elastin that cross-links to form resilient elastic fibres.

Glycoprotein: A protein with covalently attached carbohydrate moieties, often mediating cell–matrix interactions.

TGF-β (transforming growth factor β): A cytokine that controls cell proliferation, differentiation and ECM deposition, often sequestered by ECM proteins.

BMP (bone morphogenetic protein): A subgroup of the TGF-β superfamily involved in bone and cartilage development and ECM modulation.

References

1. Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells. Nature Communications (2024).
2. Fibrillin microfibril structure identifies long-range effects of inherited pathogenic mutations affecting a key regulatory latent TGFβ-binding site. Nature Structural & Molecular Biology (2023).
3. TGF-β and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature. Annual Review of Genomics and Human Genetics (2023).
4. Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors. Seminars in Cell and Developmental Biology (2018).