成纤维细胞生长因子受体2(Fibroblast growth factor receptor, FGFR2)是参与调控骨骼发育的重要分子,在调控软骨内成骨过程中发挥着重要作用。为了探讨FGFR2功能增强对小鼠下颌骨髁突生长发育的影响,文章以FGFR2功能增强型点突变(Fgfr2+/S252W)小鼠为研究对象,采用番红固绿染色研究Fgfr2+/S252W小鼠下颌骨髁突不同生长发育阶段的组织形态;利用免疫细胞化学染色和实时荧光定量PCR方法检测X型胶原(Col X)在3周龄小鼠髁突肥大软骨细胞中的表达。结果显示,1周龄、3周龄和6周龄突变型小鼠下颌骨髁突的软骨细胞层宽度都比同窝野生型窄,钙化软骨细胞层退化时间早,骨小梁钙化绿染程度深;Col X在突变型小鼠下颌骨髁突的表达高于同窝野生型小鼠(P<0.001)。结果表明,FGFR2功能增强可导致小鼠下颌骨髁突软骨层组织形态异常,抑制髁突软骨内成骨,从而导致下颌骨髁突发育畸形。
梁鑫, 张波, 刘苹, 翁土军, 张莉, 贺龙珠, 李芳菲, 屈晨, 王萍
. FGFR2功能增强对小鼠下颌骨髁突发育影响[J]. 遗传, 2015
, 37(6)
: 561
-567
.
DOI: 10.16288/j.yczz.14-370
The development of the skeleton is regulated by numerous signaling molecules expressed in epiphyseal cartilage controlling both chondrogenesis and osteogenesis such as fibroblast growth factor receptors (FGFRs). In order to explore the important effect of fibroblast growth factor receptor 2 (FGFR2) in the process of mandibular condylar growth, we introduced gain-of-function Fgfr2+/S252W mice, and investigated mandibular condylar morphology by means of safranin-o/fast green staining at the stage of 1 week, 3 weeks and 6 weeks. The mutant mice displayed narrower width of the mandibular condylar growth plate, stronger stainings of trabecular bone at the stage of 1 week, 3 weeks and 6 weeks and faster degradation of the calcified cartilage cell layer at the stage of 6 weeks. We also assessed the expression of type X collagen (Col X) in mandibular condyle at the stage of 3 weeks by immunohistochemical staining and real-time PCR. The results showed that Col X was increased in the mutant mice. In conclusion, the gain-of-function mutation in FGFR2 resulted in histopathological abnormalities and development deformity of mandibular condyle cartilage in mice, which inhibited endochondral bone formation.
[1] Martín AE, del R Pani M, Holgado NR, López Miranda LI, Meheris HE, Garat JA. Facial development disorders due to inhibition to endochondral ossification of mandibular condyle process caused by malnutrition. Angle Orthod , 2014, 84(3): 473-478.
[2] Xie YL, Zhou SR, Chen HG, Du XL, Chen L. Recent research on the growth plate: Advances in fibroblast growth factor signaling in growth plate development and disorders. J Mol Endocrinol , 2014, 53(1): T11-T34.
[3] Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet , 2004, 20(11): 563-569.
[4] Lajeunie E, Cameron R, El Ghouzzi V, De Parseval N, Journeau P, Gonzales M, Delezoide AL, Bonaventure J, Le Merrer M, Renier D. Clinical variability in patients with Apert’s syndrome. J Neurosurg , 1999, 90(3): 443-447.
[5] Yu K, Ornitz DM. Uncoupling fibroblast growth factor receptor 2 ligand binding specificity leads to Apert syndrome-likephenotypes. Proc Natl Acad Sci USA , 2001, 98(7): 3641-3643.
[6] Wang YL, Xiao R, Yang F, Karim BO, Iacovelli AJ, Cai JL, Lerner CP, Richtsmeier JT, Leszl JM, Hill CA, Yu K, Ornitz DM, Elisseeff J, Huso DL, Jabs EW. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2 +/S252W mouse. Development , 2005, 132(15): 3537- 3548.
[7] Chen L, Li D, Li CL, Engel A, Deng CX. A Ser 252 Trp substitution in mouse fibroblast growth factor receptor 2(Fgfr2) result in craniosynostosis. Bone , 2003, 33(2): 169-178.
[8] Kronenbcrg HM. Developmental regulation of the growth plate. Nature , 2003, 423(6937): 332-336.
[9] Zuscik MJ, Hilton MJ, Zhang XP, Chen D, O’Keefe RJ. Regulation of chondrogenesis and chondrocyte differentiation by stress. J Clin Invest , 2008, 118(2): 429-438.
[10] 谷志远, 胡莹, 张银凯, 冯剑颖, 胡济安. 髁突软骨的细胞分层及其功能研究. 中华口腔医学杂志, 2004, 39(5): 366.
[11] Schmid TM, Linsenmayer TF. Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. J Cell Biol , 1985, 100(2): 598-605.
[12] Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev , 2002, 16(12): 1446-1465.
[13] Yasuda T, Nah HD, Laurita J, Kinumatsu T, Shibukawa Y, Shibutani T, Minugh-Purvis N, Pacifici M, Koyama E. Muenke syndrome mutation, fgfr3 P244R , causes TMJ defects. J Dent Res , 2012, 91(7): 683-689.
[14] Lin Y, Ai SM, Chen C, Liu XL, Luo LX, Ye SB, Liang XW, Zhu Y, Yang HS, Liu YZ. Ala344Pro mutation in the Fgfr 2 gene and related clinical findings in one Chinese family with Crouzon syndrome. Mol Vis , 2012, 18: 1278-1282.
[15] Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2 mutations in Pfeiffer syndrome. Nat Genet , 1995, 9(2): 108.
