Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP‐3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10

Abstract

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 [Cl-D11 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.

Murine tissue inhibitor of metalloproteinases—4 (Timp—4): cDNA isolation and expression in adult mouse tissues1

“…Timp-2 mRNA was detected in many tissues examined, with high levels observed in lung, ovaries, brain, testes and heart. Abundant expression of Timp-3 mRNA was observed in kidney, lung, heart, brain and ovary [19,27]. In contrast to the patterns seen with Timp-\, -2 and -3, expression of Timp-4 mRNA was restricted to brain, heart, ovaries, skeletal muscle and skin.…”

92‐kDa type IV collagenase and TIMP‐3, but not 72‐kDa type IV collagenase or TIMP‐1 or TIMP‐2, are highly expressed during mouse embryo implantation

“…cDNA clones for mouse 72 kDa and 92 kDa type IV collagenases (Reponen et al, 1992(Reponen et al, ,1994, TEMP-1 (Edwards et al, 1986), TIMP-2 (Shimizu et al, 1992), and TIMP-3 (Apte et al, 1994b) have previously been isolated. For the preparation of RNA probes, the 72 kDa type IV collagenase cDNA was cut with Hue ZZZ enzyme and a 335 bp fragment from the 3' end of the cDNA (bases 2051-2386) was ligated to the pGEM-3Z vector.…”

“…TIMPS has been shown to have inhibitory activity against 72 kDa type IV collagenase (Staskus et al, 1991), but it is not known if it inhibits the 92 kDa enzyme or other metalloproteinases. The expression of TIMP-3 has been studied during the latter half of mouse development where prominant expression was seen in developing epithelial tubes, myocardium, muscle and placental trophoblasts (Apte et al, 1994b).…”

“…TIMP-2 is a 21 kDa protein capable of binding to both the latent and activated forms of 72 kDa type IV collagenase (Carmichael et al, 1986;Stetler-Stevenson et al, 1989;Goldberg et al, 1989). A novel member of the TIMP family, TIMP-3, has recently been cloned from chick (Yang and Hawkes, 1992), mouse (Apte et al, 1994b;Leco et al, 1994), and man (Apte et al, 1994a). TIMPS has been shown to have inhibitory activity against 72 kDa type IV collagenase (Staskus et al, 1991), but it is not known if it inhibits the 92 kDa enzyme or other metalloproteinases.…”

Tissue inhibitor of metalloproteinases-3 (TIMP-3) expression is increased during serum deprivation-induced neuronal apoptosis in vitro and in the G93A mouse model of amyotrophic lateral sclerosis: A potential modulator of Fas-mediated apoptosis

“…The MMPs play dynamic roles in developmental morphogenesis and in wound healing and repair during progression of tissue injury and pathologic diseases such as arthritis, cancer, and diabetes (Woessner, 1998;Visse and Nagase, 2003;Nagase et al, 2006). The activity of MMPs is regulated by four tissue inhibitors of matrix metalloproteinases (TIMPs), endogenous inhibitors of MMPs (Docherty et al, 1985;Boone et al, 1990;Apte et al, 1994;Greene et al, 1996).…”