Does MMP13 break down anything besides collagen?
Yes. Besides type II collagen, MMP13 cuts aggrecan, the water-holding molecule in cartilage, at two sites, one of them not seen with other enzymes. Purified MMP13 also broke down gelatin efficiently, unlike the other collagenases. It can cut types I and III collagen too, though five or six times less efficiently than type II.
Aggrecan
Aggrecan is the large molecule that gives cartilage its resistance to compression (Glasson 2005). In 1996, Fosang and colleagues tested MMP13 against it. MMP13 cut aggrecan in its interglobular domain, a stretch between two folded regions, at the same site other MMPs cut. It also cut at a second site no other enzyme had been seen to use (Fosang 1996).
They had a reason to look. When cartilage cells were stimulated with retinoic acid to break down their own matrix, MMP13 was the main MMP they produced (Fosang 1996).
Gelatin and other collagens
Knäuper and colleagues purified human MMP13 and tested what it would cut (Knäuper 1996):
- It preferred soluble type II collagen.
- It was five or six times less efficient on types I and III.
- It cut fibrillar type I collagen about as well as MMP-1 and MMP-8.
- Unlike those two, it broke down gelatin and two synthetic test peptides efficiently, which fits the similarity of its active site to gelatinases A and B.
When the enzyme was first cloned in 1994, the recombinant protein broke down fibrillar collagens, which supported its identity as a true collagenase (Freije 1994).
What the mice showed about aggrecan
Cutting aggrecan in a test tube doesn't mean MMP13 is the main aggrecan cutter in a joint. In mice with no MMP13, aggrecan loss four weeks after a knee injury was the same as in normal mice (Little 2009). In mice lacking working ADAMTS5, cartilage destruction was significantly reduced, and the authors named ADAMTS5 the primary aggrecanase in that model (Glasson 2005).
Mice made to produce always-active MMP13 did lose proteoglycan, the aggrecan family, along with type II collagen (Neuhold 2001). With enough MMP13, both materials suffer.
Beyond the joint
MMP13 was discovered in breast tumour tissue, and the team that cloned it found none in the normal tissues they tested (Freije 1994). Knäuper and colleagues concluded that it could play a significant role in the turnover of connective tissue matrix in the body (Knäuper 1996). The studies on this site focus on cartilage, so they say little about its other jobs.
Why the extra targets matter less
The breadth is interesting, but cartilage researchers focus on MMP13 because of collagen. Aggrecan loss is thought to be early and reversible, while type II collagen loss is considered irreversible (Li 2011). And of the MMPs, MMP13 has the highest activity against type II collagen (Li 2011). Gelatin and aggrecan can be dealt with by other enzymes. Very few can cut intact type II collagen as fast.
Other questions people ask
Which enzyme matters most for aggrecan?
In mouse studies, ADAMTS5. Mice lacking it had significantly less cartilage destruction, and mice without MMP13 lost aggrecan at the normal rate.
Is MMP13 found outside the joints?
It was first cloned from breast tumour tissue. The researchers found none in the normal tissues they tested.
Does MMP13 cut skin collagen?
It can cut types I and III collagen, but purified MMP13 was five or six times less efficient on them than on type II.
Sources
- Glasson SS, Askew R, Sheppard B et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 2005.
- Fosang AJ, Last K, Knäuper V et al. Degradation of cartilage aggrecan by collagenase-3 (MMP-13). FEBS Lett 1996.
- Knäuper V, López-Otin C, Smith B et al. Biochemical characterization of human collagenase-3. J Biol Chem 1996.
- Freije JM, Díez-Itza I, Balbín M et al. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem 1994.
- Little CB, Barai A, Burkhardt D et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 2009.
- Neuhold LA, Killar L, Zhao W et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 2001.
- Li NG, Shi ZH, Tang YP et al. New hope for the treatment of osteoarthritis through selective inhibition of MMP-13. Curr Med Chem 2011.
Read next
What does MMP13 do to cartilage?
MMP13 cuts type II collagen, the rope-like fibre that gives cartilage its strength. It cleaves each three-stranded collagen molecule at one spot, leaving a three-quarter...
MMP13 vs ADAMTS5: what's the difference?
They attack different parts of cartilage. MMP13 is the main enzyme that cuts type II collagen, the fibre network. ADAMTS5 is the main aggrecanase, cutting aggrecan, the...
MMP13 vs MMP1: what's the difference?
Both are collagenases, enzymes that can cut intact collagen, and they cut type II collagen at the same bond. MMP13 is much faster at it: at least ten times faster than...
What is MMP13?
MMP13, short for matrix metalloproteinase-13 and also called collagenase-3, is an enzyme that cuts collagen. Cartilage cells make it, and of the collagen-cutting enzymes...