Matrix Metalloproteinase-1 Associates with Intracellular Organelles and Confers Resistance to Lamin A/C Degradation during Apoptosis

Abstract

Matrix metalloproteinase (MMP)-1, commonly known as collagenase-1, and able to cleave interstitial collagens, 1 is produced by various types of cells in vitro and in vivo and its expression has been associated to inflammation, wound healing, and tumor invasion, growth, and metastasis. [2][3][4] Although the main role ascribed to MMPs has been the degradation of extracellular matrix for facilitation of cell division, migration, and differentiation, more recent work has provided evidence for the role of these enzymes in targeting nonmatrix substrates, such as cell bound cytokines, enzymes, and cell surface receptors. 5,6 It has been further suggested that there may still be more unknown substrates for these enzymes. 6 Evidence for the role of various MMPs in mediating cell functions has been given by the demonstration that gelatinases A and B (MMP-2 and MMP-9) modulate cell proliferation and differentiation, 7,8 and that inhibition of MMPs by natural inhibitors of matrix metalloproteinases (TIMPs) have diverse effects on proliferation and apoptosis in various cell types. For example, TIMPs-1 and -2 may exhibit growth factor-like activity, 9,10 while TIMP-1 can also inhibit tumor cell growth. 11 Although most MMPs are secreted and activated extracellularly, some have been shown to be anchored to the cell surface by a transmembrane domain (MT1-, MT2-, MT3-, and MT5-MMPs) and to contain a short cytoplasmic tail at the C-terminal region of the protein that facilitates their interaction with intracellular proteins that regulate cell function. 12 Furthermore, intracellular MMP-1 in platelets has been shown to activate pathways that signal phosphorylation of intracellular proteins, distributes ␤ 3 integrins to cell contact points, and primes these cells for aggregation. This provides new evidence that MMP-1 can regulate outside-in signaling events that control cell function and phenotype. 13 In addition to platelets, intracellular localization of MMP-1 has been documented in various cells, including human vascular endothelium 14 and rabbit synovial fibroblasts cultured in the presence of anti-␣5 integrin antibodies.

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

“…This net tendency to unopposed MMP activity is not mimicked by the structurally related cytokine IL-6. The effects of unopposed MMP-1 secretion by lung parenchyma at the periphery of and around the granuloma potentially include type I collagen degradation to gelatin, anti-apoptotic effects [43], and cleavage and activation of PAR (proteinase-activated receptors) [44]. MMP-3 can cleave and activate MMP-1 [4], and degrades gelatin (denatured collagen) and type IV collagen, the principal collagen component of basement membranes.…”

Metalloproteinases in idiopathic pulmonary fibrosis

“…The only study to address MMP levels pre-and post-treatment in the same individual demonstrated that combination drug therapy does not have any suppressive activity upon BALF MMP immunoreactivity [9]. This is despite the fact that a previous study suggested that steroid treatment reduces MMP-9 production in IPF patients [26]; however, in that study, patients were not individually studied consecutively pre-and post-treatment.…”

“…Alternatively, the activity of MMP-1 may be counterbalanced by tissue inhibitors, resulting in only weak activity. However, the biological roles for MMP-1, in addition to collagen degradation, include processing of cytokines, such as pro-tumour necrosis factor (TNF)-a, regulation of cell migration, and potentially cell growth [26]. These multiple biological functions of MMP-1, along with the clinical data, suggest an important role in IPF pathogenesis.…”

Matrix metalloproteinases in kidney homeostasis and diseases

“…Interestingly, MMP-3 could actually translocate into the nucleus of mammalian cells and stimulate apoptosis, and this effect is dependent on retention of its catalytic activity (117). Similarly, MMP-1 can localize to mitochondria and the nucleus of various cell types, and knockdown of MMP-1 by small interfering RNA (siRNA) sensitizes cells to apoptosis (66). Further investigation is necessary to determine whether these mechanisms impact the development of renal diseases.…”