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, higher glucose and high leptin. In animals, joint injury and mechanical stress did it too. Cells from older donors reacted more strongly to the same triggers.
The oldest and best-studied trigger is IL-1, a messenger released during inflammation. IL-1 alpha raised MMP13 in human cartilage in 1996 (Mitchell 1996). IL-1 beta and TNF-alpha raised it in human cartilage cells in a time- and dose-dependent way (Reboul 1996). Inside the cell, IL-1 needs three signalling routes, p38, JNK and NF-kB, to switch the MMP13 gene on (Mengshol 2000). The separate question on inflammation covers this in detail.
IL-1 is not the only messenger involved. Tariq Haqqi set out the case for IL-6 at the start of a talk on his lab's cell work.
OA synovial fluid contains high levels of IL-6, and IL-6 induced the expression of MMP13, and it inhibit type 2 collagen synthesis.
Researchers at the University of Auckland exposed human cartilage cells from normal-looking cartilage to IL-1 beta, hydrogen peroxide (a source of oxidative stress) or basic calcium phosphate crystals. Each raised MMP13 and ADAMTS5 and lowered SOX9, the cells' cartilage-building switch (Rong 2019).
A second study traced the crystal effect. The crystals released calcium inside the cell and activated an enzyme called CaMK2. Blocking or knocking down CaMK2 reduced the crystal-driven rise in MMP13 (Rong 2019).
Cartilage cells keep their own circadian clock. Turning down the clock gene BMAL1 in healthy cartilage cells raised MMP13 (Snelling 2016). In the Auckland work, the same triggers that raised MMP13 also disturbed the clock genes PER2 and BMAL1, and turning PER2 down partly reversed their effects (Rong 2019).
Metabolism plays a part too, again in Auckland studies of human cartilage cells:
In animals, the usual way to set off cartilage damage is a knee injury made surgically, and in those models structural cartilage damage depended on MMP13 (Little 2009). In rats, mechanical stress raised reactive oxygen species in cartilage cells, and the joint changes that followed included MMP13 expression, which the antioxidant NAC held back (Kaneko 2019).
Emma Blain explained what abnormal load does to the balance in cartilage.
This balance can tip in favor of matrix catabolism, and this is normally evident when non-physiological loads are applied. And here not only do you see a reduction in the production of these key extracellular matrix molecules, you also see an increase in the enzymes that actually break down the pre-existing extracellular matrix.
Age doesn't appear to switch MMP13 on by itself. In healthy ankle cartilage the collagenases didn't change with age (Aurich 2002). But cartilage cells from older donors made significantly more MMP13 when provoked (Forsyth 2005). Two of the control points are known: glucose acted through RUNX2, a regulator of the MMP13 gene, and IL-1 needs NF-kB to switch it on (Jain 2024; Mengshol 2000).
In lab studies, partly. Turning down the clock gene PER2 reduced MMP13 in cells from damaged cartilage, and blocking CaMK2 reduced the rise caused by calcium crystals.
The studies here can't say. Almost all were done in cartilage cells in a dish or in animals, one trigger at a time.
Not on its own. Healthy cartilage showed no age-related change in collagenases, but older cartilage cells responded more strongly to triggers.
Yes, in lab studies. The inflammatory messenger IL-1 raised MMP13 in human cartilage and cartilage cells in several studies, and TNF-alpha did too. To switch the MMP13...
In the lab, it can. University of Auckland researchers found that raising glucose from 4 to 10 mM, within the range from normal to high blood sugar, made cells from...
Not on its own. In healthy ankle cartilage from 30 donors aged 16 to 75, all four collagen-cutting enzymes were present but did not change with age. What age changed was...
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...