Table 3.
MMPs, ADAMTS, and TIMPs in arthritis pathogenesis.
| Enzymes/inhibitors | Category | Enzymes | Sources | Targets | Major functions |
|---|---|---|---|---|---|
| Metalloproteinases | |||||
| MMP-1 | Collagenases | Collagenase-1, interstitial collagenase | Monocyte, fibroblast, smooth muscle cell, chondrocyte, macrophage, endothelial cell, and keratinocyte | Collagens (I–III, VII, VIII, and X), gelatin, aggrecan, L-selectin, IL-1β, entactin, ovostatin, MMP-2, and MMP-9 | Releases MMP-9, promotes Akt dephosphorylation, degrades collagens I, II, II, III, VI, and IX and proteoglycans [66, 67]. |
| MMP-2 | Gelatinases | Gelatinase-A, 72 KDa gelatinase | Synoviocyte, CD34+ vascular endothelial cells, CD68+ macrophage, CD14+ monocyte, and stromal cell | Gelatin, collagens I, III, IV–VII, IX and X, Laminin, elastin, Fibronectin, proteoglycan, pro-MMP-13 | Increases VEGF expression and angiogenesis, promotes angiogenesis and directs degradation of cartilage matrix. |
| MMP-3 | Stromelysins | Stromelysin-1 | FLS, chondrocyte, synovial lining cell, endothelial cell | Collagens (III–V and IX), gelatin, aggrecan, perlecan, decorin, laminin, elastin, casein, osteonectin, ovostatin, entactin, plasminogen, MBP, IL-1β, MMP-2, TIMP-2, MMP-7, MMP-8, MMP-9, MMP-13, proteoglycans, and fibronectin | Degrades cartilage connexin, fibronectin, and major components of cartilage such as collagen type IV, VII, IX, and XI, activates collagenase secreted by synoviocytes, directly destroys cartilage tissue, activates interstitial collagenase, and promotes the formation of vasospasm [68]. |
| MMP-8 | Collagenases | Collagenase-2, neutrophil collagenase | Neutrophil, plasma cell, fibroblast, dentin cell, endothelial cell, bronchial epithelial cell, keratinocyte, and macrophage | Collagens (I–III, V, VII, VIII, and X), gelatin, aggrecan, and fibronectin | Degrades type I, II, and III collagens, activates MMP-2 and MMP-3, regulates the activity of TNF-α, IL-1β, and T cell membrane proteins CD2, CD4, and CD8. |
| MMP-9 | Gelatinases | Gelatinase-B, 92 kDa gelatinase | Monocyte, synoviocyte, CD34+ vascular endothelial cell, CD68+ macrophage, and neutrophil | Collagens (IV, V, VII, X, and XIV), gelatin, entactin, aggrecan, elastin, fibronectin, osteonectin, plasminogen, MBP, and IL-1β | Participates in the degradation of ECM including types IV and V collagen, proteoglycans, elastin, and gelatin and in ECM remodeling. |
| MMP-10 | Stromelysins | Stromelysin-2 | FLS, chondrocyte, and osteoblast, | Collagens (III–V), gelatin, casein, aggrecan, elastin, MMP-1, and MMP-8 | Activates MMP-1, MMP-7, MMP-8, and MMP-9 and 13 prototypes, enhances the dissolution of cartilage collagen by activating procollagenases, and enhances cartilage collagen lysis caused by IL-1 and oncostatin M. |
| MMP-12 | Other enzymes | Macrophage metalloelastase | Macrophage, monocyte, and chondrocyte | Collagen IV, gelatin, elastin, casein, fibronectin, vitronectin, laminin, entactin, fibrinogen, fibrin, and plasminogen | Degrades type IV collagen, fibronectin, laminin, vitronectin, proteoglycan, chondroitin sulfate, and myelin basic protein and activates MMP-2 and MMP-3. |
| MMP-13 (interstitial collagenase) | Collagenases | Collagenase-3 | Chondrocyte, FLS, and macrophage | Collagens (I–IV, IX, X, and XIV), gelatin, plasminogen, aggrecan, perlecan, fibronectin, osteonectin, and MMP-9 | Degrades collagen fibers of types I, II, III, V, and XI as well as basement membrane proteoglycans. |
| MMP-14 | MT-MMP | MT1-MMP, MT-MMP-1 | Macrophage, myeloid cell, FLS, and CD68+ osteoclast | Collagens (I–III), gelatin, casein, fibronectin, laminin, vitronectin, entactin, proteoglycans, and MMP-2 and 13 | Promotes FLS to invade cartilage. MT1-MMP degrades collagen types I, II, and III, laminin-1 and laminin-5, fibronectin, vitronectin, fibrin, and aggrecan, and activates pro-MMP-2 and pro-MMP-13 on the cell surface [69, 70]. |
|
| |||||
| ADAMTS [71, 72] | |||||
| ADAMTS-1 | Aggrecanases | METH-1, Aggrecanase-3 | Chondrocyte, macrophage | Aggrecan, versican | Cleaves the proteoglycan versican. |
| ADAMTS-4 | Aggrecanases | Aggrecanase-1 | FLS, chondrocyte | Aggrecan, crevican, COMP, decorin, fibromodulin, and versican | Cleaves aggrecan. |
| ADAMTS-5 | Aggrecanases | Aggrecanase-2, ADAMTS-11 | FLS, stromal cell | Aggrecan | Cleaves aggrecan. |
| ADAMTS-7 | None | ADAMTS-7B | FLS, chondrocyte | COMP, α2M | Degrades cartilage oligomeric matrix protein (COMP). |
| ADAMTS-9 | None | KIAA1312 | FLS | Aggrecan, versican | Degrades aggrecan and has the potential to cleave other cartilage molecules. |
| ADAMTS-12 | None | None | FLS, chondrocyte | Aggrecan, COMP, and α2M | Degrades COMP. |
|
| |||||
| Inhibitors | |||||
| TIMP-1 | Glycoprotein | None | Macrophage, connective tissue cell, chondrocyte, FLS, T cell, and monocyte | MMP-3, MMP-9, MMP-14, MMP-16, MMP-19, MMP-24, ADAM10, and pro-MMP-9 | Weak inhibition of MMP-14, MMP-16, MMP-19, and MMP-24 and ADAM10. Inhibits pro-MMP interactions with pro-MMP-9, formation of synovial blood vessels, activation of MMP-3 and 9, and synovial vascular invasion in RA. |
| TIMP-2 | Glycoprotein | None | Chondrocyte, FLS, T cell, and monocyte | ADAM12, pro-MMP-2, and MMP-9 | Inhibits all the MMPs (prevents overactivation of MMP-9), ADAM12, and pro-MMP interactions with pro-MMP-2. |
| TIMP-3 | Glycoprotein | None | FLS, chondrocyte, macrophage, and monocyte | ADAM10, ADAM12, ADAM17, ADAM28, and ADAM33; ADAMTS-1-2 and 4-5; pro-MMP-2,9; and MMP-2, MMP-9, and MMP-13 | Inhibits all the MMPs and ADAM10, ADAM12, ADAM17, ADAM28, and ADAM33; ADAMTS-1, ADAMTS-4, and ADAMTS-5, ADAMTS-2 (weak); and pro-MMP interactions with pro-MMP-9 and pro-MMP-2. |
| TIMP-4 | Glycoprotein | None | FLS, endothelial cell, T cell, and monocyte (less) | ADAM17d, ADAM28, and ADAM33 and pro-MMP-2 | Inhibits most of the MMPs and ADAM17d and ADAM28, ADAM33 (weak), pro-MMP interactions with pro-MMP-2) and development of arthritis. |
Abbreviations: ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs; COMP: cartilage oligomeric matrix protein; GEP: granulin-epithelin precursor; TIMP: tissue inhibitor of metalloproteinases; vWFCP: von Willebrand factor cleaving protease; α2M: α2-macroglobulin.