The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain

Abstract

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer's disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer's patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer's-linked amyloid-beta (Aβ) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Aβ. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype. However, recent advances in stem cell and in vitro approaches offer novel insights into understanding TIMP-3 pathology in the retina-brain axis, which has so far not been collectively examined. We propose that TIMP-3 activities could extend beyond its hitherto supposed functions to cause age-related changes and disease in these organs.

Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD)

“…Although several molecular pathways are involved, such as the accumulation of oxidative products or dysregulation in the vascular and immune system [15] among others, AMD pathophysiology is yet to be fully understood. Using this framework, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) could play an important role in its etiopathogenesis, as well as its regulator systems, which are composed mainly of the matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) [16][17][18][19].…”

“…The involvement of ADAMs by VEGF-A activation in vascular endothelial cells suggests their role in regulating the neovascularization of the retina [79]. The proteolytic ability of MMPs and ADAMs is directly regulated by TIMPs, which bind to them and inhibit their activities [16].…”

“…In addition, MMPs play a central role in the direct activation of signaling molecules, such as tumor necrosis factor (TNF) and other cytokines; MMPs therefore contribute to various aspects of immunity [ 48 ]. A detailed classification of MMPs and TIMPs, based on their substrates, general biological effect, localization in the eye, and processes in which they take part, is provided in the Supplementary Table S1 [ 16 , 17 , 32 , 38 , 41 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ].…”

“…TIMP-1 inhibits the activity of the membrane-type MMPs (MT-MMPs such as MMP-14), TIMP-2 and TIMP-3 can bind to all types of MMPs and also inhibit several ADAM and ADAMTS family members, and TIMP-4 is able to inhibit the activity of MMP-1, MMP-2, MMP3, MMP-7, and MMP-9 [ 84 , 87 , 88 ]. TIMP-3 is found in chromosome 22q12.3 and is enclosed within an intron of the gene, synapsin 3 (SYN3), while TIMP-1 and TIMP-4 are located within the introns of synapsin 1 (SYN1) and synapsin 2 (SYN2), respectively; however, MMP-2 seems not to have this feature [ 16 ].…”

In vitro stem cell modelling demonstrates a proof‐of‐concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy

“…The family of TIMP proteins are expressed ubiquitously within the body and play a myriad of biological roles through their ability to reversibly inhibit matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase (ADAMs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) [8,9]. TIMP3 encodes a 24 kDa glycoprotein consisting of two domains: the N-terminal domain is involved in MMP inhibition (and at high levels can induce apoptosis in RPE), whereas the C-terminal domain binds directly to VEGFR2 (KDR), inhibiting VEGF binding and downstream PI3K/Akt and Ras/Raf/ERK signalling in choroidal endothelial cells [1].…”