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

Objective To decipher the role of gene candidates involved in pulmonary hypertension (PH) associated with systemic sclerosis (SSc). 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 (ECs) issued from patients with SSc-PH, SSc without PH and controls. Expression of identified candidates was assessed by quantitative sandwich ELISA in the serum and by immunohistochemistry in lesional lung tissue. Their functional importance was then evaluated in fos-related antigen-2 (Fra-2) transgenic mice that spontaneously develop SSc-like features associated with an intense pulmonary vascular remodeling. Results Microarray experiments revealed that Matrix metalloproteinase-10 (MMP10) was the top upregulated gene in SSc-PH EPC-derived ECs. Circulating pro-MMP10 serum concentrations were markedly increased in patients with SSc-PH compared to SSc patients without PH and controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found both in lungs of SSc-PH patients and Fra-2 transgenic mice. Daily treatment of Fra-2 mice with neutralizing anti-MMP10 antibodies did not significantly affect pulmonary fibrosis, but reversed established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival and the PDGF signaling axis. Conclusion Gene expression profiling of EPC-derived ECs identified MMP10 as a novel candidate in SSc-PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc-PH, and its blockade alleviates PH in the Fra-2 mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder. This article is protected by copyright. All rights reserved.