{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMatrix metallopeptidase 21 (MMP-21) is emerging as a key extracellular protease with critical developmental roles. Notably, genetic studies have shown that recessive mutations in MMP21 disrupt the normal establishment of left–right asymmetry in the embryo, leading to heterotaxy and abnormal cardiac looping. These findings, together with additional high‐throughput sequencing data in human heterotaxy cases, suggest that MMP-21–mediated extracellular matrix remodeling is essential for proper laterality during vertebrate embryogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various human malignancies, MMP-21 expression is frequently altered and appears to serve as both a marker of tumor differentiation and a prognostic indicator. In pancreatic adenocarcinoma, MMP-21 is expressed preferentially in well-differentiated cancer cells and is upregulated by epidermal growth factor, suggesting that its expression reflects a state of cellular differentiation rather than invasive potential. Similar trends have been observed in esophageal and gastric cancers, as well as oral squamous cell carcinomas and colorectal cancers, where increased MMP-21 levels correlate with tumor invasion, metastasis, and poor overall survival. Interestingly, studies in Merkel cell carcinoma and breast cancer genetic analyses indicate that MMP-21 may also be linked with less aggressive tumor behavior or serve as a genetic risk factor."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn epidermal tissues, MMP-21 is detected in differentiated keratinocytes as well as in subsets of fibroblasts and macrophages present in benign skin disorders. Its expression in these cells is modulated by differentiation signals such as increased calcium and retinoic acid, and it appears to participate in terminal keratinocyte differentiation rather than in the regulation of proliferation or apoptosis. These observations underline a potential role for MMP-21 in tissue remodeling and maintenance of epithelial homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in development and cancer, MMP-21 has been implicated in other pathological contexts. For example, polymorphism studies suggest that specific coding variants of MMP-21 may influence the severity of HIV-associated neurocognitive disorder, with certain alleles conferring a protective effect. In addition, altered levels of MMP-21 in systemic sclerosis patients have been proposed as serum biomarkers that link extracellular matrix remodeling to pathogenic fibrosis in this connective tissue disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zeev Perles, Sungjin Moon, Asaf Ta-Shma, et al. 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