Metalloprotease inhibitor TIMP proteins control FGF-2 bioavailability and regulate skeletal growth

Saw, Sanjay; Aiken, Alison; Fang, Hui; McKee, Trevor D.; Bregant, Sarah; Sánchez, Otto; Chen, Yan; Weiss, Ashley; Dickson, Brendan C.; Czarny, Bertrand; Sinha, Ankit; Fosang, Amanda J.; Dive, Vincent; Waterhouse, Paul; Kislinger, Thomas; Khokha, Rama

doi:10.1083/jcb.201906059

Cited by 17 publications

(21 citation statements)

References 78 publications

(97 reference statements)

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“…Several proteases are regulated by an activation cascade by which different proteases that are secreted as inactive pro-forms or bound to the ECM are released and activated by other proteases 9 . The activity of proteases is counterbalanced by protease inhibitors (e.g., tissue inhibitor of metalloproteinases, TIMPs) 95 . The substrates of the different proteases are still not completely understood.…”

Section: Changes In Ecm Modification and Organisation In Cancermentioning

confidence: 99%

Concepts of extracellular matrix remodelling in tumour progression and metastasis

et al. 2020

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Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.

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Section: Changes In Ecm Modification and Organisation In Cancermentioning

confidence: 99%

Concepts of extracellular matrix remodelling in tumour progression and metastasis

et al. 2020

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“…MMP14 deficiency leads to a deregulation of collagen turnover, thereby leading to dwarfism and impairment of bone development in mice ( Holmbeck et al., 1999 ). TIMP KO mice show abnormalities in bone growth, such as long bone growth plate closure defects, limb shortening, epiphyseal distortion, and widespread chondrodysplasia ( Saw et al., 2019 ). Nevertheless, the roles that ECM remodeling factors like the TIMPs and MMPs play in human osteogenesis remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs

et al. 2021

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Costello syndrome (CS) is an autosomal dominant disorder caused by mutations in HRAS. Although CS patients have skeletal abnormalities, the role of mutated HRAS in bone development remains unclear. Here, we use CS induced pluripotent stem cells (iPSCs) undergoing osteogenic differentiation to investigate how dysregulation of extracellular matrix (ECM) remodeling proteins contributes to impaired osteogenesis. Although CS patient-derived iPSCs develop normally to produce mesenchymal stem cells (MSCs), the resulting CS MSCs show defective osteogenesis with reduced alkaline phosphatase activity and lower levels of bone mineralization. We found that hyperactivation of SMAD3 signaling during the osteogenic differentiation of CS MSCs leads to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1, and TIMP2. CS MSCs undergoing osteogenic differentiation also show reduced b-catenin signaling. Knockdown of TIMPs permits normal differentiation of CS MSCs into osteoblasts and enhances b-catenin signaling in a RUNX2-independent manner. Thus, this study demonstrates that enhanced TIMP expression induced by hyperactivated SMAD3 signaling impairs the osteogenic development of CS MSCs via an inactivation of b-catenin signaling.

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“…Our studies with RPE cells suggest that the increase in HA in these cells is likely a consequence of increased FGF. A recent study [47] suggests that TIMP proteins can control FGF-2 bioavailability in skeletal tissue and the same might be true of multiple tissues leading to systemic increase in HA in the plasma. The exact mechanism by which TIMP3 regulates FGF bioavailability in the RPE is currently unknown, but it is highly likely that the TIMP-metalloproteinase axis likely has a key role.…”

Section: Discussionmentioning

confidence: 99%

Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy

Wolk

Hatipoglu

Cutler

et al. 2020

Cells

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Sorsby's fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related macular degeneration (AMD). The objective of this study was to gain further insight into the molecular mechanism(s) by which mutant TIMP3 induces CNV. In this study we demonstrate that hyaluronan (HA), a large glycosaminoglycan, is elevated in the plasma and retinal pigment epithelium (RPE)/choroid of patients with AMD. Mice carrying the S179C-TIMP3 mutation also showed increased plasma levels of HA as well as accumulation of HA around the RPE in the retina. Human RPE cells expressing the S179C-TIMP3 mutation accumulated HA apically, intracellularly and basally when cultured long-term compared with cells expressing wildtype TIMP3. We recently reported that RPE cells carrying the S179C-TIMP3 mutation have the propensity to induce angiogenesis via basic fibroblast growth factor (FGF-2). We now demonstrate that FGF-2 induces accumulation of HA in RPE cells. These results suggest that the TIMP3-MMP-FGF-2-HA axis may have an important role in the pathogenesis of CNV in SFD and possibly AMD.

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Metalloprotease inhibitor TIMP proteins control FGF-2 bioavailability and regulate skeletal growth

Cited by 17 publications

References 78 publications

Concepts of extracellular matrix remodelling in tumour progression and metastasis

Concepts of extracellular matrix remodelling in tumour progression and metastasis

Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs

Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy

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