Matrix Metalloproteinase-10: A Novel Biomarker for Idiopathic Pulmonary Fibrosis

Akihiko Sokai; Tomohiro Handa; Kiminobu Tanizawa; Toru Oga; Kazuko Uno; Tatsuaki Tsuruyama; Takeshi Kubo; Kohei Ikezoe; Yoshinari Nakatsuka; Kazuya Tanimura; Shigeo Muro; Toyohiro Hirai; Sonoko Nagai; Kazuo Chin; Michiaki Mishima

Disclosures

Respiratory Research. 2015;16(120) 

In This Article

Discussion

In the present study, several MMPs, including MMP-10, were significantly elevated in the sera of the patients with IPF compared with the patients with COPD and controls. MMP-10 and -7 correlated significantly with several physiological indices, including %FVC and %DLCO. Furthermore, a higher serum MMP-10 level was associated with both clinical deterioration within 6 months and overall survival. In IPF lungs, MMP-10 was expressed in alveolar macrophages and epithelial cells.

MMPs reportedly play an important role in the pathogenesis of IPF.[13] Previous studies have demonstrated that both BALF and serum MMP-1 were elevated in IPF.[14,15] The biological roles of MMP-1 suggest that it may play an important role in the pathogenesis of IPF.[13,24] MMP-3-knockout mice and MMP-7-knockout mice do not develop pulmonary fibrosis induced by bleomycin,[25,26] suggesting that MMP-3 and -7 may also act as mediators of pulmonary fibrosis. Indeed, MMP-1 and -7 were also increased in the patients with IPF compared with controls in the present study.

In previous studies, however, few MMPs reportedly correlated with disease severity and prognosis despite their possible roles in the pathogenesis of IPF. Serum MMP-7 concentrations were elevated in patients with subclinical interstitial lung disease (ILD) and correlated negatively with %FVC and %DLCO, whereas no significant correlation was noted between serum MMP-1 and pulmonary function.[15] High levels serum MMP-7 and SP-A may predict shorter survival in patients with IPF.[27] In the present study, we demonstrated a correlation between MMP-7 and pulmonary function, including %FVC and %DLCO, that was consistent with the findings of the previous studies. Furthermore, we observed that serum MMP-10 correlated more significantly with disease severity and prognosis in patients with IPF compared with MMP-7.

MMP-10, like MMP-3 and -11, is categorized into stromelysins and degrades a variety of ECM proteins, including proteoglycans, laminin, fibronectin, gelatins, and collagen types III, IV, V, and IX.[18,28,29] MMP-10 activates other MMPs, including proMMP-1, -7, -8, and -9.[17,30] MMP-10 expression is observed in injured and remodeling tissues as well as in various types of cells, including the keratinocytes present in skin wounds, injured colonic tissue, and different cells in injured liver.[18,31,32] MMP-10 is one of the most well-known MMPs involved in the pathogenesis of carcinomas. Elevated levels of MMP-10 protein have been observed in tumors, including non-small cell lung cancer,[33] head and neck squamous cell carcinoma,[34] bladder transitional cell carcinoma,[35] epithelial skin cancer,[36] renal cell carcinoma,[37] and colon adenocarcinoma.[38]

In experimental models, MMP-10 was elevated via exposure to cerium oxide or silica.[39,40] A previous study evaluating the degree of pulmonary fibrosis induced by ultrafine amorphous silica also demonstrated that the expression of MMP-10 was associated with pulmonary fibrosis.[41] Transforming growth factor-β (TGF-β) is elevated in IPF and exerts profibrotic effects, such as fibroblast differentiation, suppression of myofibroblast apoptosis, ECM induction, and regulation of the balance between MMPs and tissue inhibitors of MMPs.[42,43] Furthermore, TGF-β up-regulates several MMPs, including MMP-10, in epithelial cells.[44,45] Therefore, pulmonary fibrosis may be induced by TGF-β through several pathways, including MMP-10. Taken together, MMP-10 may be involved in the pathogenesis of pulmonary fibrosis, as with other MMPs, such as MMP-1 and -7.

We observed that in human fibrotic lungs, the expression of MMP-10 was localized to the alveolar epithelial cells, macrophages, and peripheral bronchiolar epithelial cells. MMP-10 reportedly localized to fibrotic regions and alveolar macrophages in cerium oxide-treated lungs and silica-induced pulmonary fibrosis.[39,40] However, the localization of MMP-10 has not been investigated in IPF. Most MMPs, including MMP-1, -2, -7, and -9, are expressed in alveolar epithelial cells, whereas other MMPs, including MMP-2 and -9, may be found in the fibroblastic foci in IPF.[2] Immunohistochemical results and the significant correlation between serum and BALF MMP-10 observed in the present study suggest that serum MMP-10 in IPF is derived from the epithelial cells and macrophages in the lungs.

Despite a more significant correlation of serum MMP-10 with disease severity and prognosis compared with other MMPs, serum concentrations of MMP-10 were lower than many other MMPs in IPF. Although the reason was unclear, the abundant MMP-10 expression in IPF lungs visualized by immunological staining and the significant association between serum MMP-10 and clinical features may suggest that MMP-10 plays a significant role in the pathogenesis of IPF.

There were some limitations to the present study. First, the number of patients was small. Additional prospective studies with larger numbers of patients are necessary to validate the role of MMP-10 as a biomarker for IPF. Second, we did not investigate MMPs in other ILDs, such as nonspecific interstitial pneumonia, connective tissue disease-associated ILD, and OP. MMP-7 is reportedly elevated in other ILDs, such as cryptogenic OP and systemic sclerosis-associated ILD;[46–48] therefore, the up-regulation of MMP-10 may not be specific to IPF. Third, some patients had already been treated with prednisolone, an immunosuppressant, or pirfenidone at baseline. Pirfenidone, an antifibrotic agent that suppresses TGF-β, may affect the expression of MMPs, including MMP-10.[49] However, the prognostic significance of serum MMP-10 persisted after excluding the treated patients.

We concluded that MMP-10 is a novel biomarker for IPF, correlates with disease severity, and predicts disease progression. Additional studies are necessary to elucidate the functional role of MMP-10 and other MMPs in the pathogenesis of IPF.

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