In two main ways. Cells release MMP13 as an inactive proenzyme that must be cut before it works, and the body makes its own inhibitors, the TIMPs. TIMP-1, TIMP-2 and TIMP-3 each blocked active MMP13 one to one in the lab. Healthy cartilage keeps its collagen-cutting enzymes at steady levels.
MMP13's protein sequence carries the stretch that keeps MMPs latent, or switched off, alongside its zinc-binding site (Freije 1994). Knäuper and colleagues showed how the switch flips. Purified procollagenase-3 weighed about 60 kDa. Activated by a chemical or by another enzyme, stromelysin, it passed through a 50 kDa intermediate and was then trimmed to a final active enzyme of 48 kDa (Knäuper 1996). Activation by trypsin removed the enzyme's end section quickly, and its ability to cut collagen fell (Knäuper 1996). Reboul and colleagues found that human cartilage cells make collagenase-3 as a proenzyme (Reboul 1996).
So a cell can make MMP13 without it being active. Something has to cut it first.
TIMPs, tissue inhibitors of metalloproteinases, are the body's built-in MMP blockers. The human genome has four, TIMP-1 to TIMP-4 (Brew 2010). They were first described as MMP inhibitors, and they also block several ADAM and ADAMTS enzymes, the family that includes the aggrecan-cutter ADAMTS5 (Brew 2010).
Active MMP13 was inhibited in a one-to-one fashion by TIMP-1, TIMP-2 and TIMP-3 (Knäuper 1996). Each TIMP molecule takes out one enzyme molecule. A 2010 review describes TIMPs as key regulators of the metalloproteinases that degrade the matrix around cells (Brew 2010). They do more than block enzymes. The same review lists effects on cell growth, migration and cell death that don't depend on metalloproteinases, and mouse studies that deleted single TIMP genes showed how much these molecules matter in health and disease (Brew 2010).
In healthy ankle cartilage from 30 donors aged 16 to 75, all four collagenases were present, their levels didn't change with age, and type II collagen synthesis and breakdown stayed at a steady state throughout life (Aurich 2002). Whatever holds the balance, it held across six decades in that study.
Ali Mobasheri put the healthy and diseased states side by side at the start of a 2016 talk.
We have homeostasis between extracellular matrix synthesis and degradation, and in osteoarthritis we have predominantly extracellular matrix degradation and cartilage collagen fragmentation.
Provocations push cartilage cells to make more MMP13. IL-1, TNF-alpha, oxidative stress, calcium crystals, glucose and leptin have all done it in human cartilage cells (Reboul 1996; Rong 2019; Rong 2019; Jain 2024; Primrose 2023). Older cells respond more strongly (Forsyth 2005). Disturbing the cells' internal clock gene BMAL1 raised MMP13 too (Snelling 2016). The questions on what switches MMP13 on and on inflammation cover these.
Tom Appleton adds a trigger the lab studies leave out, too little load.
If you're not getting any loading at all, no compression whatsoever, you are actually going to decrease your protein production, you're not going to maintain that matrix, and you're going to turn on inflammatory pathways that break down the tissue. So you're going to start digesting your own organ if you're not being stimulated.
A few studies have measured TIMPs as well as MMPs:
These show that the balance between MMPs and their inhibitors can be shifted in cells and animals. They don't show it shifting in people.
Tissue inhibitor of metalloproteinases. Humans have four, TIMP-1 to TIMP-4.
TIMPs block several ADAM and ADAMTS enzymes as well as MMPs. ADAMTS5 belongs to the ADAMTS family.
No. Cartilage cells make it as an inactive proenzyme, which has to be cut to a smaller active form before it can work.
In human cartilage cells, MMP13 rose in response to inflammatory messengers such as IL-1, oxidative stress, calcium phosphate crystals, a disrupted cell body clock...
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...
In animal and lab studies, yes. AKBA, the lead boswellic acid, suppressed MMP13 in rats with chemically induced knee damage, and a frankincense extract lowered MMP13...
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...