CKIP-1对小鼠皮肤纤维化及TGF-β1和collagen-1表达的影响
|
摘要
目的:分析CKIP-1基因敲除后对皮肤纤维化的作用,并检测其对TGF-β1和collagen-1表达的影响。方法:取6月龄CKIP-1基因敲除小鼠作为实验组,与同窝雄性野生型小鼠进行对照,观察小鼠皮肤大体形态变化,再通过HE和masson染色分析皮肤的组织学改变,最后通过免疫组化检测皮肤纤维化相关的重要细胞因子TGF-β1和collagen-1的分子表达情况。结果:CKIP-1基因敲除小鼠皮肤较硬、弹性较差,镜下观察皮肤角化增加,表皮层和真皮层增厚,纤维扭曲、增粗,胶原含量显著增加,免疫组化检测发现TGF-β1和collagen-1分子表达增加,且TGF-β1在表皮及真皮交界处表达增加最为显著。结论:小鼠CKIP-1基因敲除后皮肤出现明显的纤维化改变,可能与TGF-β1表达增加相关。
Objective: To study the effects of Casein kinase 2 interacting protein 1(CKIP-1) on skin fibrosis and the expression of TGF-β1 and collagen-1 in mice. Methods: 6-month-old mice with CKIP-1 knockout(WO) were used as the experimental group, the wild-type littermates were used as the controls. The macroscopical changes of skins of the mice were observed, HE and masson staining were used to evaluate the histological feature. The expression of TGF-β1 and collagen-1 was investigated by immunohistochemistry. Results: WO mice showed harder but less elastic of the skin compared with controls. HE and masson staining showed hyperkeratosis of skin, thickened eplidermis and dermis, in which fibers were tortuous and thick, and the contents of collagen increased. Immunohistochemistry showed that the expression of TGF-β1 and collagen-1 increased, especially in dermal-eplidermal junction. Conclusion: There are fibrotic changes in the skin of CKIP-1 knockout mice, possibly associated with the increased expression of TGF-β1 and collagen-1.
Objective: To study the effects of Casein kinase 2 interacting protein 1(CKIP-1) on skin fibrosis and the expression of TGF-β1 and collagen-1 in mice. Methods: 6-month-old mice with CKIP-1 knockout(WO) were used as the experimental group, the wild-type littermates were used as the controls. The macroscopical changes of skins of the mice were observed, HE and masson staining were used to evaluate the histological feature. The expression of TGF-β1 and collagen-1 was investigated by immunohistochemistry. Results: WO mice showed harder but less elastic of the skin compared with controls. HE and masson staining showed hyperkeratosis of skin, thickened eplidermis and dermis, in which fibers were tortuous and thick, and the contents of collagen increased. Immunohistochemistry showed that the expression of TGF-β1 and collagen-1 increased, especially in dermal-eplidermal junction. Conclusion: There are fibrotic changes in the skin of CKIP-1 knockout mice, possibly associated with the increased expression of TGF-β1 and collagen-1.
引文
[1] Coentro JQ, Pugliese E, Hanley G, et al. Current and upcoming therapies to modulate skin scarring and fibrosis[J]. Adv Drug Deliv Rev, 2018, S0169-409X(18): 30207.
[2] Klingberg F, Hinz B, White ES. The myofibroblast matrix: Implications for tissue repair and fibrosis[J]. J Pathol, 2013, 229(2): 298-309.
[3] Lovvorn HN 3rd, Cheung DT, Nimni ME, et al. Relative distribution and crosslinking of collagen distinguish fetal from adult sheep wound repair[J]. J Pediatr Surg, 1999, 34(1): 218-223.
[4] O'Boyle CP, Shayan-Arani H, Hamada MW. Intralesional cryotherapy for hypertrophic scars and keloids: A review[J]. Scars Burn Heal, 2017, 3: 1-9.
[5] Hu HH, Chen DQ, Wang YN, et al. New insights into TGF-β/Smad signaling in tissue fibrosis[J]. Chem Biol Interact, 2018, 292: 76-83.
[6] Lu K, Yin X, Weng T, et al. Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1[J]. Nat Cell Biol, 2008, 10(8): 994-1002.
[7] Guo B, Zhang G, Tang T, et al. Increased CKIP-1 expression vs decreased TGF-beta receptor 1 expression during aging-induced cartilage degeneration in female rats[J]. Bone, 2010, 47: S419.
[8] 朱学俊, 孙建方. 皮肤病理学与临床的联系[M]. 3版. 北京: 北京大学出版社, 2007: 804.
[9] 王成, 荣艳华, 沈余明, 等. 正常皮肤与增生性瘢痕中Ⅰ型和Ⅲ型胶原的含量与比例[J]. 山东大学学报, 2016, 54(11): 64-66.
[10] Heldin CH, Moustakas A. Signaling Receptors for TGF-β Family Members[J]. Cold Spring Harb Perspect Biol, 2016, 8(8)pii: a022053.
[11] Walton KL, Johnson KE, Harrison CA. Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis[J]. Front Pharmacol, 2017, 8: 461.
[12] Tu Y, Lineaweaver WC, Zhang F. TGF-β1 -509C/T polymorphism and susceptibility to keloid disease: A systematic review and meta-analysis[J]. Scars Burn Heal, 2017, 3: 2059513117709943.
[13] Liu J, Liang C, Guo B, et al. Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging[J]. Aging Cell, 2017,16(2): 360-376.
[14] Liu J, Lu C, Wu X, et al. Targeting osteoblastic casein kinase-2 interacting protein-1 to enhance Smad-dependent BMP signaling and reverse bone formation reduction in glucocorticoid-induced osteoporosis[J]. Sci Rep, 2017, 7: 41295.
[15] Asano Y, Ihn H, Yamane K, et al. Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts[J]. J Clin Invest, 2004, 113(2): 253-264.
[16] 刘富伟, 胡奥, 张浚睿, 等. Ckip-1对小鼠耳廓软骨发育的影响[J]. 实用口腔医学杂志, 2018, 34(3): 293-297.
[17] 王礼鑫. 前列腺上皮细胞及其表达CKIP-1对前列腺部尿道创面中成纤维细胞TGF-β1和α-SMA表达的影响[D]. 贵阳: 贵州医科大学, 2018.
[18] Gong W, Chen C, Xiong F, et al. CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells[J]. Biochem Pharmacol, 2016, 116: 140-152.
[19] Ling S, Sun Q, Li Y, et al. CKIP-1 inhibits cardiac hypertrophy by regulating class II histone deacetylase phosphorylation through recruiting PP2A[J]. Circulation, 2012, 126(25): 3028-3040.
[20] 刘玲, 陈敏亮, 雷永红, 等. 表皮干细胞表型的成纤维样细胞在瘢痕中的表达[J]. 中国美容医学, 2009, 18(5): 645-647.
[2] Klingberg F, Hinz B, White ES. The myofibroblast matrix: Implications for tissue repair and fibrosis[J]. J Pathol, 2013, 229(2): 298-309.
[3] Lovvorn HN 3rd, Cheung DT, Nimni ME, et al. Relative distribution and crosslinking of collagen distinguish fetal from adult sheep wound repair[J]. J Pediatr Surg, 1999, 34(1): 218-223.
[4] O'Boyle CP, Shayan-Arani H, Hamada MW. Intralesional cryotherapy for hypertrophic scars and keloids: A review[J]. Scars Burn Heal, 2017, 3: 1-9.
[5] Hu HH, Chen DQ, Wang YN, et al. New insights into TGF-β/Smad signaling in tissue fibrosis[J]. Chem Biol Interact, 2018, 292: 76-83.
[6] Lu K, Yin X, Weng T, et al. Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1[J]. Nat Cell Biol, 2008, 10(8): 994-1002.
[7] Guo B, Zhang G, Tang T, et al. Increased CKIP-1 expression vs decreased TGF-beta receptor 1 expression during aging-induced cartilage degeneration in female rats[J]. Bone, 2010, 47: S419.
[8] 朱学俊, 孙建方. 皮肤病理学与临床的联系[M]. 3版. 北京: 北京大学出版社, 2007: 804.
[9] 王成, 荣艳华, 沈余明, 等. 正常皮肤与增生性瘢痕中Ⅰ型和Ⅲ型胶原的含量与比例[J]. 山东大学学报, 2016, 54(11): 64-66.
[10] Heldin CH, Moustakas A. Signaling Receptors for TGF-β Family Members[J]. Cold Spring Harb Perspect Biol, 2016, 8(8)pii: a022053.
[11] Walton KL, Johnson KE, Harrison CA. Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis[J]. Front Pharmacol, 2017, 8: 461.
[12] Tu Y, Lineaweaver WC, Zhang F. TGF-β1 -509C/T polymorphism and susceptibility to keloid disease: A systematic review and meta-analysis[J]. Scars Burn Heal, 2017, 3: 2059513117709943.
[13] Liu J, Liang C, Guo B, et al. Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging[J]. Aging Cell, 2017,16(2): 360-376.
[14] Liu J, Lu C, Wu X, et al. Targeting osteoblastic casein kinase-2 interacting protein-1 to enhance Smad-dependent BMP signaling and reverse bone formation reduction in glucocorticoid-induced osteoporosis[J]. Sci Rep, 2017, 7: 41295.
[15] Asano Y, Ihn H, Yamane K, et al. Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts[J]. J Clin Invest, 2004, 113(2): 253-264.
[16] 刘富伟, 胡奥, 张浚睿, 等. Ckip-1对小鼠耳廓软骨发育的影响[J]. 实用口腔医学杂志, 2018, 34(3): 293-297.
[17] 王礼鑫. 前列腺上皮细胞及其表达CKIP-1对前列腺部尿道创面中成纤维细胞TGF-β1和α-SMA表达的影响[D]. 贵阳: 贵州医科大学, 2018.
[18] Gong W, Chen C, Xiong F, et al. CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells[J]. Biochem Pharmacol, 2016, 116: 140-152.
[19] Ling S, Sun Q, Li Y, et al. CKIP-1 inhibits cardiac hypertrophy by regulating class II histone deacetylase phosphorylation through recruiting PP2A[J]. Circulation, 2012, 126(25): 3028-3040.
[20] 刘玲, 陈敏亮, 雷永红, 等. 表皮干细胞表型的成纤维样细胞在瘢痕中的表达[J]. 中国美容医学, 2009, 18(5): 645-647.