Abstract
Morphogenesis of the upper lip and palate is a complex process involving highly regulated interactions between epithelial and mesenchymal cells. Genetic evidence in humans and mice indicates the involvement of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) in cleft lip palate (CLP) aetiology. This study investigated whether expression of MMP-2, MMP-8, MMP-9, TIMP-2, and TIMP-4, which are essential for the upper lip and palate fusion, is dysregulated in children with CLP. Oral mucosa tissue samples were obtained from patients with complete unilateral (CU) CLP (n = 25) and complete bilateral (CB) CLP (n = 19) during corrective plastic surgery and in unaffected control subjects (n = 10). MMPs and TIMPs expression was assessed by immunohistochemistry, and the data were analyzed using the Kruskal - Wallis test with the Bonferroni correction. In CLP patients, MMP-2, TIMP-2 immunoreactivity in the oral mucosa was seen to have a few to abundant structures, but the overall number of MMP-2, TIMP-2-positive structures was greater than that in controls (P < 0.01). The total number of TIMP-4, MMP-9-positive cells showed a significant decrease in the CBCLP compared with that of CUCLP (P < 0.001). MMP-8 expression trends in the CLP group were similar to those of the control group. The results suggest that TIMP-4 and MMP-9 are the main ECM remodeling regulatory proteins expressed in CUCLP affected tissues of the oral mucosa. The increased expression of MMP-2 and TIMP-2 in CLP tissues implicates these factors in the regulation of cell migration during ECM turnover independently of different types of clefts. Investigation of MMP and TIMP expression in tissue samples from patients with CLP appears to be a promising approach to the etiopathogenesis of CLP.
Highlights
Craniofacial anomalies, in particular cleft lip and palate (CLP), are the most prevalent birth defects in humans with a worldwide frequency of 1 in 500 to 1000 livebirths[1]
This study investigated the expression of matrix metalloproteinases (MMPs)-2, MMP8, MMP-9, TIMP-2, and TIMP-4 in complete unilateral (CU), complete bilateral (CB) CLP to identify possible changes in signaling pathways that could lead to the abberant maxillofacial morphogenesis observed in CLP
CBCLP MMP-2 and MMP-8-positive structures were detected in all CBCLP cases, and the presence of MMP-2, MMP8-positive epithelial cells was a few to abundant (Fig. 1, 2)
Summary
Craniofacial anomalies, in particular cleft lip and palate (CLP), are the most prevalent birth defects in humans with a worldwide frequency of 1 in 500 to 1000 livebirths[1]. Normal development of the lip and palate involves a series of highly coordinated morphogenetic events that include cell migration, differentiation, growth, apoptosis, active fusion, and subsequent breakdown of the medial edge epithelium, as well as breakdown of the basement membrane. Any disturbance in these events may cause irreversible changes resulting in the development of facial clefts. The increased expression of MMP-2 and TIMP-2 in CLP tissues implicates these factors in the regulation of cell migration during ECM turnover independently of different types of clefts.
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