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 piece and a one-quarter piece. It also cuts aggrecan, the cushioning molecule. In mice, too much active MMP13 was enough to erode joint cartilage.
Type II collagen is a triple helix, three protein strands wound together. Mitchell and colleagues showed in 1996 that MMP13 cuts it to give the characteristic three-quarter and one-quarter fragments, at the same bond MMP-1 cuts. MMP13 then makes a second cut, trimming three amino acids off the end of the shorter piece (Mitchell 1996).
Speed is what sets it apart. In that study MMP13 turned over type II collagen at least ten times faster than MMP-1 (Mitchell 1996). A second 1996 study measured it at about five times faster (Reboul 1996). Purified MMP13 also preferred type II collagen to types I and III (Knäuper 1996).
Collagen isn't MMP13's only target in cartilage. Aggrecan is the large molecule that holds water and lets cartilage resist being squashed (Glasson 2005). MMP13 cuts aggrecan at a site other MMPs also use, and at a second site no other enzyme had been seen to cut (Fosang 1996). When cartilage cells in the lab were pushed to break down their own matrix, MMP13 was the main MMP they made (Fosang 1996).
In 2001 a team engineered mice whose cartilage made a human MMP13 that was always switched on. After birth their joints developed changes like those of human joint disease, including erosion of the cartilage, loss of proteoglycan (the aggrecan family) and excessive cutting of type II collagen. The joint lining thickened as well (Neuhold 2001).
The reverse experiment came in 2009. Mice with no MMP13 had a knee injury made surgically. At four weeks they had lost as much aggrecan as normal mice, but at eight weeks they had less erosion of the cartilage on the shin bone (Little 2009). The authors concluded that structural cartilage damage in that model depended on MMP13 activity. Other changes, the enlarging of cartilage cells and bony outgrowths at the joint edge, still happened without it (Little 2009).
Researchers draw a sharp line between the two kinds of damage. Losing aggrecan is thought to be an early and reversible step, while losing type II collagen is considered irreversible and a key step in cartilage losing its structure and function (Li 2011). Mitchell's group made the same point in 1996, describing collagen breakdown as an important step towards irreversible tissue damage (Mitchell 1996).
The reason is turnover. The half-life of cartilage collagen has been estimated at 117 years, against 15 for skin collagen (Verzijl 2000). Radiocarbon dating of knee cartilage found virtually no replacement of the collagen network after the skeleton stops growing (Heinemeier 2016). On those figures, a fibre MMP13 cuts is unlikely to be replaced soon. One group has reported faster turnover of soluble type II collagen in ankle cartilage (Hsueh 2019), which the question on whether cartilage grows back covers.
Peter Torzilli, who studies how enzymes cut collagen under mechanical load, makes a narrower point about the cut molecule itself.
… as a molecule and as a structural element that resists tension, especially in cartilage, when it gets cleaved the cells cannot repair it. The cells could produce more collagen, but they can't repair the broken collagen.
Cartilage cells make MMP13. The cells lining the joint did not, in Reboul's study (Reboul 1996). Inflammatory messengers raised it: IL-1 alpha in Mitchell's study (Mitchell 1996), and IL-1 beta and TNF-alpha in Reboul's, with the effect depending on time and dose (Reboul 1996).
The studies on this page measured cartilage, collagen fragments and enzyme levels, not pain. They don't show whether MMP13 itself causes pain.
In mice without MMP13, bony outgrowths still formed at the joint edge after injury, so MMP13 was not needed for those changes in that model.
Very little, on the radiocarbon evidence. Dating of adult knee cartilage found virtually no replacement of the collagen network after skeletal maturity, in healthy and damaged cartilage alike. One group has reported faster turnover of soluble type II collagen in ankle cartilage.
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...
It depends which part is damaged. Reviews describe losing aggrecan, the water-holding molecule in cartilage, as an early and reversible step, and losing type II collagen...
Its collagen barely does, on most measurements. Radiocarbon dating of knee cartilage from 23 people found virtually no replacement of the collagen network after the...
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...