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      Collagenase IV plays an important role in regulating hair cycle by inducing VEGF, IGF-1, and TGF-β expression

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          Abstract

          Background

          It has been reported that collagenases (matrix metalloproteinase 2 [MMP-2] and matrix metalloproteinase 9 [MMP-9]) are associated with hair cycle, whereas the mechanism of the association is largely unknown.

          Methods

          The mice were randomly allocated into four groups: saline, and 5, 10, and 15 nM SB-3CT. Immunohistochemical analysis was employed to examine MMP-2 and MMP-9 protein. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay were performed to determine mRNA and protein levels of VEGF, IGF-1, TGF-β, and GAPDH. Growing hair follicles from anagen phase III–IV were scored based on hematoxylin and eosin staining. Hair regrowth was also evaluated.

          Results

          Results showed that mRNA expressions of enzymes changed with a peak at late anagen and a trough at telogen after depilation. Immunostaining showed that the highest expression of MMP-2 was more than that of MMP-9, and the highest expression of enzymes changed during anagen. The localizations of MMP-2 changed from dermal papilla, keratinocyte strand, out of root sheath, and basal plate at early anagen, to hair bulb, inner root sheath, and outer root sheath at late anagen. The localization of MMP-9 changed from partial keratinocyte to dermal papilla at early anagen and to outer root sheath at late anagen. VEGF, IGF-1, and TGF-β have been shown to regulate hair growth. We found mRNA and protein expressions of VEGF and IGF-1 fluctuated with a peak at anagen and a decrease at catagen to telogen. In contrast, mRNA and protein expressions of TGF-β changed with highest and lowest levels at anagen and telogen, respectively. With selective inhibitor of collagenase IV, SB-3CT, mice showed significant suppressed hair growth and decreased expression of VEGF, IGF-1, and TGF-β. The MMPs agonist also significantly increased expression of VEGF, IGF-1, and TGF-β. Meanwhile, SB-3CT treatment significantly suppressed hair growth.

          Conclusion

          All these data suggest that the type IV collagenases, MMP-2 and MMP-9, play important roles in hair cycle, and this could be mediated by induced expression of VEGF, IGF-1, and TGF-β.

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          Most cited references 24

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          Control of hair growth and follicle size by VEGF-mediated angiogenesis.

          The murine hair follicle undergoes pronounced cyclic expansion and regression, leading to rapidly changing demands for its vascular support. Our study aimed to quantify the cyclic changes of perifollicular vascularization and to characterize the biological role of VEGF for hair growth, angiogenesis, and follicle cycling. We found a significant increase in perifollicular vascularization during the growth phase (anagen) of the hair cycle, followed by regression of angiogenic blood vessels during the involution (catagen) and the resting (telogen) phase. Perifollicular angiogenesis was temporally and spatially correlated with upregulation of VEGF mRNA expression by follicular keratinocytes of the outer root sheath, but not by dermal papilla cells. Transgenic overexpression of VEGF in outer root sheath keratinocytes of hair follicles strongly induced perifollicular vascularization, resulting in accelerated hair regrowth after depilation and in increased size of hair follicles and hair shafts. Conversely, systemic treatment with a neutralizing anti-VEGF antibody led to hair growth retardation and reduced hair follicle size. No effects of VEGF treatment or VEGF blockade were observed in mouse vibrissa organ cultures, which lack a functional vascular system. These results identify VEGF as a major mediator of hair follicle growth and cycling and provide the first direct evidence that improved follicle vascularization promotes hair growth and increases hair follicle and hair size.
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            Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma.

            Gastric carcinoma is still a major leading cause of cancer death in East Asia. Since angiogenesis is a necessary condition for invasion and metastasis, its regulation is of essential significance. Expressions of MMP-2, MMP-9 and VEGF were examined with microarray of gastric carcinoma tissue samples (n = 249) by immunostaining. In addition, microvessel density (MVD) was assessed after labelling with the anti-CD34 antibody. Data were cross-compared with clinicopathological parameters of tumors, including PTEN expression. Expressions of MMP-2, MMP-9 and VEGF were positively correlated with tumour size, depth of invasion, lymphatic and venous invasion, lymph node metastasis, UICC staging and MVD of gastric carcinomas (p < 0.05).VEGF expression was positively linked with levels of MMP-2 and MMP-9 (p < 0.05), but negatively with PTEN (p < 0.05). The latter was also inversely associated with the MVD in gastric carcinomas (p < 0.05). MMP-2, MMP-9 and VEGF largely contribute to the angiogenesis and progression of gastric carcinomas. PTEN might inhibit the processes by down-regulating VEGF expression. These parameters should be regarded as good markers to indicate pathobiological behaviours of gastric carcinomas.
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              Keratinocyte growth factor is required for hair development but not for wound healing.

              Keratinocyte growth factor (KGF), also known as fibroblast growth factor 7 (FGF7), is synthesized by skin fibroblasts. However, its mitogenic activity is on skin keratinocytes, where it is the most potent growth factor identified thus far. To explore KGF's function in vivo, we used embryonic stem cell technology to generate mice lacking KGF. Over time, their fur developed a matted appearance, very similar to that of the rough mouse, whose recessive mutation maps at or near the KGF locus on mouse chromosome 2. In contrast to the recently reported transforming growth factor-alpha (TGF-alpha) and FGF5 knockouts, which showed defects in the follicle outer-root sheath and the hair growth cycle, respectively, the hair defect in the KGF knockout seemed to be restricted to the cells giving rise to the hair shaft. Thus, we have uncovered a third, and at least partially nonoverlapping, growth factor pathway involved in orchestrating hair follicle growth and/or differentiation. Surprisingly, the absence of KGF resulted in no abnormalities in epidermal growth or wound healing. This was true even when we engineered double knockout mice, null for both KGF and TGF-alpha, two factors that are increased dramatically in the normal wound-healing process. Whereas we found no evidence of compensatory changes at the mRNA level of wounded knockout mice, these data imply that the regulation of epidermal growth is complex and involves a number of growth stimulatory factors that go beyond what are thought to be the major paracrine and autocrine growth factors. We suggest that the redundancy in epidermal growth and wound healing is likely to stem from the vitality of these functions to the organism, a feature that is not a consideration for the hair follicle.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                25 September 2015
                : 9
                : 5373-5383
                Affiliations
                Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
                Author notes
                Correspondence: Zhi-Qi Hu, Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, People’s Republic of China, Tel +86 20 6164 1866, Fax +86 20 6164 1866, Email doctorhzq@ 123456yeah.net
                Article
                dddt-9-5373
                10.2147/DDDT.S8912
                4590320
                © 2015 Hou et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                telogen, mmp-2, sb-3ct, mmp-9

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