Apte S S, Hayashi K, Seldin M F, Mattei M G, Hayashi M, Olsen B R
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
Dev Dyn. 1994 Jul;200(3):177-97. doi: 10.1002/aja.1002000302.
Remodeling of the extracellular matrix (ECM) is an essential component of normal development and is also involved in the pathogenesis of arthritis and the spread of cancer. The matrix metalloproteinases and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play an important role in this context. We have isolated mouse cDNA clones encoding a novel member of the TIMP family, designated TIMP-3. We have assigned the Timp-3 locus to the [C1-D1] region of mouse chromosome 10 using both genetic and cytogenetic methods. The conceptual translation product of the Timp-3 cDNA shows a high degree of similarity with ChIMP-3, a recently cloned chicken metalloproteinase inhibitor, as well as significant structural similarity with the amino acid sequences of the previously isolated members of this family, TIMP-1 and TIMP-2. The pattern of expression of Timp-3 in the developing mouse embryo is distinct from that previously reported for Timp-1. Timp-3 is expressed in cartilage and skeletal muscle, in myocardium, in the skin, oral and nasal epithelium, in the newborn mouse liver, in the epithelium of some tubular structures such as the developing bronchial tree, oesophagus, colon, urogenital sinus, bile duct, in the kidney, salivary glands, and in the choroid plexus of the brain. The patterns of Timp-3 expression in surface epithelia and in the epithelial lining of many tubular organs suggests that TIMP-3 may be involved in regulating ECM remodeling during the folding of epithelia and during the formation, branching, and expansion of epithelial tubes. In the mouse placenta, expression is seen in the trophoblast, raising the possibility that TIMP-3 may be involved in regulating trophoblastic invasion of the uterus. We propose a role for TIMP-3 in musculoskeletal and cardiac development, in the morphogenesis of certain epithelial structures, and placental implantation.
细胞外基质（ECM）的重塑是正常发育的重要组成部分，也与关节炎的发病机制和癌症的扩散有关。基质金属蛋白酶及其天然抑制剂——金属蛋白酶组织抑制剂（TIMPs），在这一过程中发挥着重要作用。我们分离出了编码TIMP家族一个新成员的小鼠cDNA克隆，命名为TIMP-3。我们运用遗传和细胞遗传学方法将Timp-3基因座定位到小鼠10号染色体的[C1-D1]区域。Timp-3 cDNA的概念翻译产物与最近克隆的鸡金属蛋白酶抑制剂ChIMP-3高度相似，并且与该家族先前分离出的成员TIMP-1和TIMP-2的氨基酸序列也有显著的结构相似性。Timp-3在发育中的小鼠胚胎中的表达模式与先前报道的Timp-1不同。Timp-3在软骨和骨骼肌、心肌、皮肤、口腔和鼻上皮、新生小鼠肝脏、一些管状结构的上皮（如发育中的支气管树、食管、结肠、泌尿生殖窦、胆管）、肾脏、唾液腺以及脑脉络丛中表达。Timp-3在表面上皮和许多管状器官的上皮衬里中的表达模式表明，TIMP-3可能参与调节上皮折叠过程中以及上皮管形成、分支和扩张过程中的ECM重塑。在小鼠胎盘中，滋养层可见Timp-3表达，这增加了TIMP-3可能参与调节滋养层对子宫侵袭的可能性。我们提出TIMP-З在肌肉骨骼和心脏发育、某些上皮结构的形态发生以及胎盘植入过程中发挥作用。
