Tenascin-X deficiency causes a clinically distinct, recessive form of the Ehlers-Danlos syndrome. This finding indicates that factors other than the collagens or collagen-processing enzymes can cause the syndrome and suggests a central role for tenascin-X in maintaining the integrity of collagenous matrix.

Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb-/- mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb-/- mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb-/- mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb-/- and wildtype cells was similar, Tnxb-/- fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.

Small airways are the major site of airflow obstruction in chronic obstructive pulmonary disease (COPD). This is attributed to loss of elastin in alveoli and fibrosis in small airways. In the present study, it was hypothesised that changes to elastic fibres in alveoli might be paralleled by a similar reduction in elastic fibres in small airways.Tissue blocks from patients who had lobectomy for bronchial carcinoma were studied. Patients were classified as COPD (forced expiratory volume in one second (FEV1) ,80% predicted, FEV1/ forced vital capacity (FVC) ,0.7) or controls (FEV1 o80% pred, FEV1/FVC o0.7). Elastic fibres were visualised using Elastic van Gieson staining and the volume fraction (v/f) of elastic fibres was determined as a percentage of tissue volume using point counting. Elastic fibre networks were also visualised by confocal microscopy.The v/f for elastic fibres in alveoli was 18.6% for COPD and 32.8% in controls. In the airways the v/f was 14.6% for COPD and 25.5% in controls. FEV1% predicted was correlated with v/f in both alveoli and small airways.The volume fraction of elastic fibres was reduced to a similar extent in small airways and alveoli in chronic obstructive pulmonary disease and both were correlated with the extent of airflow obstruction. Loss of elastic fibres in small airways may contribute to the development of airflow obstruction in chronic obstructive pulmonary disease.

Tenascin-C (TNC) is an extracellular matrix glycoprotein of unknown function that is highly expressed in adult lung parenchyma following acute lung injury (ALI). Here we report that mice lacking TNC are protected from interstitial fibrosis in the bleomycin model of ALI. Three weeks after exposure to bleomycin, TNC-null mice had accumulated 85% less lung collagen than wild-type mice. The lung interstitium of TNC-null mice also appeared to contain fewer myofibroblasts and fewer cells with intranuclear Smad-2/3 staining, suggesting impaired TGF-β activation or signaling. In vitro, TNC-null lung fibroblasts exposed to constitutively active TGF-β expressed less α-smooth muscle actin and deposited less collagen I into the matrix than wild-type cells. Impaired TGF-β responsiveness was correlated with dramatically reduced Smad-3 protein levels and diminished nuclear translocation of Smad-2 and Smad-3 in TGF-β-exposed TNC-null cells. Reduced Smad-3 in TNC-null cells reflects both decreased transcript abundance and enhanced ubiquitin-proteasome-mediated protein degradation. Together, these studies suggest that TNC is essential for maximal TGF-β action after ALI. The clearance of TNC that normally follows ALI may restrain TGF-β action during lung healing, whereas prolonged or exaggerated TNC expression may facilitate TGF-β action and fibrosis after ALI.

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