Novel Transcription Factor-Like Function of Human Matrix Metalloproteinase 3 Regulating the CTGF/CCN2 Gene

Abstract

Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of matricellular proteins and also has been designated Hcs24, FISP12, IGFBP8, IGFBP-rP2, ␤IG-M2, and ecogenin. The other CCN proteins include Cyr61/CCN1, NOV/CCN3, WISP1/CCN4, WISP2/CCN5, and WISP3/CCN6 (5, 26, 38, 39) as well, and they are structurally and functionally related glycoproteins involved in cell differentiation, proliferation, adhesion, migration, and the formation of the extracellular matrix. These matricellular functions of CCNs are involved in physiological processes such as wound healing, angiogenesis, morphogenesis, and embryogenesis as well as in pathological states including fibrotic disorders, cancer, and arthritis.Earlier we showed that CCN2 promotes endochondral ossification by acting on chondrocytes, osteoblasts, and endothelial cells (35,37,46). For example, CCN2 promotes physiological chondrocytic proliferation and extracellular matrix (ECM) formation. We also reported the regeneration of defects in articular cartilage in rat knee joints following treatment with recombinant CCN2 (36). Furthermore, ctgf-null mice were dead on delivery and were characterized by defective angiogenesis, the derangement of endochondral ossification, and dysmorphisms that occurred as a result of impaired chondrocyte proliferation and an abnormal ECM composition within the hypertrophic zone (24).Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are involved in the remodeling and turnover of the ECM in physiological processes such as angiogenesis, wound healing, embryogenesis, and morphogenesis as well as in pathological states including cancers, myocardial infarction, fibrotic disorders, rheumatism, and osteoarthritis (33, 49). Cartilage is a connective tissue that is constructed by chondrocytes embedded within an ECM predominantly composed of collagens and proteoglycans. ECM remodeling is achieved by regulating the production and degradation of specific ECM components. MMPs, which comprise a large family of enzymes with differential abilities to degrade specific ECM components, play a vital role in this process. MMPs also cleave growth factors and their binding proteins, thereby activating or inhibiting specific signaling events (15). Of note, the expression and role of MMP3 have been investigated in the pathological status of articular cartilage, such as in osteoarthritis and rheumatism (1,52).Recent study has demonstrated the existence and functions of intracellular MMPs and tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 accumulates in the cellular nuclei in association with the cell cycle (54). Alternative splicing and promoter usage generate an intracellular MMP11 isoform directly translated as an active MMP (31). MMP2 is found in the nuclei of cardiac myocytes and is capable of cleaving poly-(ADP-ribose) polymerase (PARP) in vitro (28). MMP3 also is detected in the nuclei of hepatocytes and is involved in apop-* Corresponding author. Mailing address:

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

“…Intracellular existence of matrix metalloproteinase and its activation under various conditions have been reported (23,32,33). In the previous study, we demonstrated that MMP3 is activated in DA cells treated with 1-methyl-4-phenylpyridinium, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-mediated DA neuronal degeneration in the mouse SN was largely attenuated in Mmp3 null mice (22).…”

Involvement of matrix metalloproteinases in the growth plate response to physiological mechanical load

“…CTGF expression and activity are regulated by MMP-3 (11,20). This protein is known to be involved in endochondral ossification (39) and plays a critical role during bone regeneration (26).…”

“…Connective tissue growth factor (CTGF/CCN2) is regulated by MMP-3 in two ways: 1) it cleaves CTGF protein into two ϳ20-kDa fragments that are thought to have distinct functions (20); and 2) it acts intracellularly to enhance CTGF transcription by directly binding to the CTGF promoter (11). MMP-3 has been shown to upregulate the expression of CTGF in the human chondrocyte cell line HCS-2/8 (11).…”

“…MMP-3 has been shown to upregulate the expression of CTGF in the human chondrocyte cell line HCS-2/8 (11). CTGF promotes proliferation, maturation, and hypertrophy of growth-plate chondrocytes during endochondral ossification (39).…”

Influência do estrógeno, progesterona e testosterona nos níveis de expressão e na distribuição de ADAMTS-1 (uma desintegrina e metaloproteinase com domínios trombospondinas 1) em células mamárias humanas normais e tumorais.

“…Neste estudo, ficou claro como uma protease que antes conhecidamente de matriz extracelular, com função intracelular, pode estar no núcleo celular, envolvida com a regulação da transcrição de genes. Outro estudo, MMP-3 se localiza no núcleo, e promove a transcrição de genes em uma linhagem de células de condrócitos (EGUCHI et al, 2008).…”