Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

Objective To elucidate the role of gene candidates involved in pulmonary hypertension ( PH ) associated with systemic sclerosis ( SS c). Methods Gene candidates were identified through microarray experiments performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in endothelial progenitor cell ( EPC )–derived endothelial cells ( EC s) obtained from patients with SS c‐associated PH , patients with SS c without PH , and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme‐linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos ‐related antigen 2–transgenic (Fra‐2–Tg) mice that spontaneously develop SS c‐like features associated with an intense pulmonary vascular remodeling. Results Microarray experiments revealed that the matrix metalloproteinase 10 ( MMP ‐10) gene was the top up‐regulated gene in SS c‐associated PH EPC ‐derived EC s. Circulating serum pro MMP 10 concentrations were markedly increased in patients with SS c‐associated PH compared to SS c patients without PH and healthy controls. Consistent with these observations, a strong MMP 10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SS c‐associated PH and in the lungs of Fra‐2–Tg mice. Daily treatment of Fra‐2–Tg mice with neutralizing anti‐ MMP 10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet‐derived growth factor signaling axis. Conclusion Gene expression profiling of EPC ‐derived EC s identified MMP 10 as a novel candidate gene in SS c‐associated PH . MMP 10 is overexpressed in the serum and pulmonary arteries of patients with SS c‐associated PH , and its blockade alleviates PH in the Fra‐2–Tg mouse model. MMP 10 appears to be a prospective treatment target for this devastating disorder.