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 molecule that resists squashing. Researchers describe aggrecan loss as early and reversible and collagen loss as irreversible. Mouse studies link each enzyme to cartilage damage.
Cartilage is a network of type II collagen fibres holding aggrecan, a large molecule that gives the tissue its resistance to compression (Eyre 2002; Glasson 2005). Each material has its own main enzyme. MMP13 is the major collagenase in damaged cartilage, with the highest activity against type II collagen (Li 2011). ADAMTS5, short for a disintegrin and metalloproteinase with thrombospondin motifs 5, is the major aggrecanase (Jiang 2021; Rong 2019).
Both are metalloproteinases, but from different families. MMP13 is a matrix metalloproteinase; ADAMTS5 belongs to the ADAMTS family (Glasson 2005).
Emma Blain summed up the split while describing a published animal study of an unstable joint.
Increased expression of the enzymes that break down … the matrix metalloproteinases, which break down the collagen, and the ADAMTSs, the aggrecanases, which break down the proteoglycans.
The difference that matters most is what happens after the cut. Aggrecan loss is thought to be an early and reversible process. Type II collagen loss is considered irreversible (Li 2011). Cartilage collagen is barely replaced in adults (Heinemeier 2016), so the collagen side of the damage is the one that accumulates. Some researchers argue the collagen turns over faster than that in some joints, such as the ankle (Hsueh 2019).
Each enzyme has its own landmark mouse study:
Read together, removing ADAMTS5 reduced cartilage destruction, and removing MMP13 reduced erosion even with aggrecan gone (Glasson 2005; Little 2009).
In human cartilage cells, the triggers that raise one often raise the other. Higher glucose raised both MMP13 and ADAMTS5 in cells from damaged cartilage (Jain 2024). Inflammation, oxidative stress and calcium crystals raised both while unsettling the cells' clock (Rong 2019). Leptin is an exception worth noting. It raised ADAMTS5 at 20 and 40 ng/ml but MMP13 only at 40, and through a different route (Primrose 2023).
A 2021 review listed senescence, inheritance, inflammation and mechanical stress as drivers of ADAMTS5 overactivity, through pathways that include RUNX2 and NF-kB (Jiang 2021). RUNX2 and NF-kB also control MMP13 (Jain 2024; Mengshol 2000).
The division of labour isn't absolute. MMP13 cuts aggrecan too, at a site shared with other MMPs and at one of its own (Fosang 1996). And the body's own TIMP inhibitors block both families: they were first known as MMP inhibitors and also block several ADAM and ADAMTS enzymes (Brew 2010).
Both are being studied as targets. Antibodies and small molecules against ADAMTS5 have shown benefit before human trials, in cells and animals (Jiang 2021). Reviews of MMP13 inhibitors include dual inhibitors aimed at MMP13 and aggrecanase together (Li 2011). Neither enzyme has yet been the target of an approved medicine.
Fiona Watt adds a caution that applies to any cartilage enzyme target, though her example is the aggrecanases rather than MMP13.
A classic example of that is a group of enzymes called aggrecanases, where we know from mouse models if we block those genetically at least that the disease gets better. But remember there's a flip side to this, so there are also pathways that seem to be really important for repair and regeneration, and we've seen that too, and there obviously taking those out would actually make the disease worse.
It depends on which damage you mean. ADAMTS5 drives aggrecan loss, which is described as reversible; MMP13 drives type II collagen loss, which is described as irreversible.
A disintegrin and metalloproteinase with thrombospondin motifs. ADAMTS5 is also called aggrecanase-2.
Yes. A 1996 study found MMP13 cleaves aggrecan at a site other MMPs use and at a new site of its own.
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...
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...
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...
Because it acts at the step reviews call irreversible. MMP13 is the main enzyme cutting type II collagen in damaged cartilage, and that collagen renews very slowly. Mice...