Collagenase 3 is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''MMP13''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
It is a member of the
matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form.
MMP-13 has a predicted molecular weight around 54 kDa. It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the hemopexin-like domain . Although the actual mechanism has not been described, the hemopexin domain participates in collagen degradation, the catalytic domain alone being particularly inefficient in collagen degradation. During embryonic development, MMP-13 is expressed in the skeleton as required for restructuring the collagen matrix for bone mineralization. In pathological situations it is highly overexpressed; this occurs in human carcinomas, rheumatoid arthritis and osteoarthritis.
Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The protein encoded by this gene cleaves type II collagen more efficiently than types I and III. It may be involved in articular cartilage turnover and cartilage pathophysiology associated with osteoarthritis. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3.
Regulation
Transcriptional regulation of MMP-13 is tightly controlled due to its potent proteolytic capacity. There are several binding domains for various
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
including
AP-1,
PEA-3 and
OSE-2 as well as a sequence with homology to a TGF-β inhibitory element (TIE). Moreover, several cytokines and growth factors have been demonstrated to affect ''Mmp13'' gene expression, including
parathyroid hormone,
IGF-1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called " sulfa ...
,
TGF-β, hepatocyte growth factor and many inflammatory cytokines such as
IL-1α and
IL-1β.
The upstream regulatory region of the Mmp13 gene contains a number of
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
binding sites but it was recently discovered that there is a conserved forkhead response element (FHRE) consensus sequence for
FOXO3a in the human, mouse and rat Mmp13
promoter. Endogenous FOXO3a activation results in marked upregulation of Mmp13 expression which is capable of promoting
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
degradation and
apoptotic cell death.
Clinical Relevance
MMP-13 has long been a protein of interest in the context of
osteoarthritis
Osteoarthritis is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone. A form of arthritis, it is believed to be the fourth leading cause of disability in the world, affect ...
and
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
.
The role of MMP-13 has also been thoroughly examined in
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
, specifically in potentially reducing the
collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
content of the fibrous cap.
References
Further reading
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External links
* The
MEROPS online database for peptidases and their inhibitors
M10.013
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Matrix metalloproteinases
Human proteins
EC 3.4.24