Targeting Dysregulation of Metalloproteinase Activity in Osteoarthritis.

Published on Aug 9, 2020in Calcified Tissue International3.423
· DOI :10.1007/S00223-020-00739-7
Kazuhiro Yamamoto17
Estimated H-index: 17
(University of Liverpool),
David J. Wilkinson11
Estimated H-index: 11
(University of Liverpool),
George Bou-Gharios51
Estimated H-index: 51
(University of Liverpool)
Sources
Abstract
Metalloproteinases were first identified as collagen cleaving enzymes and are now appreciated to play important roles in a wide variety of biological processes. The aberrant activity and dysregulation of the metalloproteinase family are linked to numerous diseases including cardiovascular and pulmonary diseases, chronic wounds, cancer, fibrosis and arthritis. Osteoarthritis (OA) is the most prevalent age-related joint disorder that causes pain and disability, but there are no disease-modifying drugs available. The hallmark of OA is loss of articular cartilage and elevated activities of matrix-degrading metalloproteinases are responsible. These enzymes do not exist in isolation and their activity is tightly regulated by a number of processes, such as transcription, proteolytic activation, interaction with their inhibitors, cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu. Here, we describe the functions and roles of metalloproteinase family in OA pathogenesis. We highlight recent studies that have illustrated novel mechanisms regulating their extracellular activity and impairment of such regulations that lead to the development of OA. We also discuss how to stop or slow down the degenerative processes by targeting aberrant metalloproteinase activity, which may in future become therapeutic interventions for the disease.
📖 Papers frequently viewed together
20 Citations
88 Citations
2019
3 Authors (Mingcai Zhang, ..., Jinxi Wang)
References143
Newest
#1Hiroyuki Nakamura (Kanazawa University)H-Index: 61
#2Phoung Vo (Imperial College London)H-Index: 2
Last. George Bou-Gharios (University of Liverpool)H-Index: 51
view all 5 authors...
A key feature of osteoarthritis is the gradual loss of articular cartilage and bone deformation, resulting in the impairment of joint function. The primary cause of cartilage destruction is considered to be the presence of elevated proteases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs). However, clinically tested global MMP inhibitors have low efficacy that may be due to their lack of selectivity. We previously demonstrate...
7 CitationsSource
#1Yuka Sawai (Kyoto University)H-Index: 1
#2Manabu Miyata (Kyoto University)H-Index: 13
Last. Akitaka Tsujikawa (Kyoto University)H-Index: 60
view all 15 authors...
Quality of single optical coherence tomography angiography (OCTA) images of myopic choroidal neovascularisation (mCNV) is poorer than in averaged images, although obtaining averaged images takes much time. This study evaluated the clinical usefulness of novel denoising process for depicting mCNV. This study included 20 eyes of 20 patients with mCNV. Ten en face images taken in a 3 × 3 mm macular cube were obtained from outer-retina-to-choriocapillaris layer. Three image types were prepared for a...
34 CitationsSource
#1Salvatore Santamaria (Imperial College London)H-Index: 14
#2Kazuhiro Yamamoto (University of Liverpool)H-Index: 17
: Aggrecan is a major matrix component of articular cartilage, and its dysregulated proteolysis is a crucial event in the pathogenesis of arthritis. Aggrecanases, members of ADAMTS family, play a pivotal role in aggrecan degradation with ADAMTS-4 and ADAMTS-5 being key enzymes. Cleavage events mediated by ADAMTSs are highly specific and very well characterized; therefore, it is possible to investigate aggrecanolysis by using antibodies reacting with the new N- and C-termini of the cleavage produ...
5 CitationsSource
#1Courtney M. Mazur (University of California, Berkeley)H-Index: 5
#2Jonathon J. Woo (UCSF: University of California, San Francisco)H-Index: 2
Last. Tamara Alliston (University of California, Berkeley)H-Index: 32
view all 13 authors...
Osteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicu...
23 CitationsSource
#1Carsten Scavenius (AU: Aarhus University)H-Index: 17
#2Emil Poulsen (AU: Aarhus University)H-Index: 3
Last. Jan J. Enghild (AU: Aarhus University)H-Index: 75
view all 9 authors...
Destruction of the cartilage matrix in joints is an important feature of arthritis. Proteolytic degradation of cartilage glycoproteins can contribute to the loss of matrix integrity. Human inter-α-inhibitor (IαI), which stabilizes the extracellular matrix, is composed of the light-chain serine proteinase inhibitor bikunin and two homologous heavy chains (HC1 and HC2) covalently linked through chondroitin 4-sulfate. Inflammation promotes the transfer of HCs from chondroitin 4-sulfate to hyalurona...
3 CitationsSource
#1Sanjay Saw (Princess Margaret Cancer Centre)H-Index: 3
#1Sanjay Saw (Princess Margaret Cancer Centre)H-Index: 3
Last. Rama Khokha (Princess Margaret Cancer Centre)H-Index: 84
view all 16 authors...
Regulated growth plate activity is essential for postnatal bone development and body stature, yet the systems regulating epiphyseal fusion are poorly understood. Here, we show that the tissue inhibitors of metalloprotease (TIMP) gene family is essential for normal bone growth after birth. Whole-body quadruple-knockout mice lacking all four TIMPs have growth plate closure in long bones, precipitating limb shortening, epiphyseal distortion, and widespread chondrodysplasia. We identify TIMP/FGF-2/I...
7 CitationsSource
#1Adrian M D Falconer (Newcastle University)H-Index: 4
#2Chun Ming Chan (Newcastle University)H-Index: 3
Last. David J. Wilkinson (Newcastle University)H-Index: 11
view all 9 authors...
: The collagenase subfamily of matrix metalloproteinases (MMPs) have important roles in the remodeling of collagenous matrices. The proteinase-activated receptor (PAR) family has a unique mechanism of activation requiring proteolysis of an extracellular domain forming a neo-N terminus that acts as a tethered ligand, a process that has been associated with the development of arthritis. Canonical PAR2 activation typically occurs via a serine proteinase at Arg36-Ser37, but other proteinases can cle...
6 CitationsSource
#1Ioannis Kanakis (University of Liverpool)H-Index: 10
#2Ke Liu (University of Liverpool)H-Index: 13
Last. George Bou-Gharios (University of Liverpool)H-Index: 51
view all 7 authors...
BACKGROUND:Cartilage destruction in osteoarthritis (OA) is mediated mainly by MMPs and ADAMTSs. The therapeutic candidature of targeting aggrecanases has not yet been defined in joints where spontaneous OA arises due to genetic susceptibility, without a traumatic or load- induced aetiology such as the STR/Ort mouse. Nor do we know the long-term effect of aggrecanase inhibition on bone. METHODS:Using the STR/Ort spontaneously OA background, we have generated transgenic mice that overexpress [-1A]...
4 CitationsSource
#1David Young (Newcastle University)H-Index: 84
#2Matt J. Barter (Newcastle University)H-Index: 20
Last. David J. Wilkinson (Newcastle University)H-Index: 11
view all 3 authors...
Metalloproteinases remain important players in arthritic disease, in part because members of this large enzymatic family, namely matrix metalloproteinase-1 (MMP-1) and MMP-13, are responsible for the irreversible degradation of articular cartilage collagen. Although direct inhibition of MMPs fell out of vogue with the initial clinical disappointment of the first generation of compounds, interest in other mechanisms that control these important enzymes has always been maintained. Since these enzy...
18 CitationsSource
#1David J. Wilkinson (Newcastle University)H-Index: 11
#2Maria Del Carmen Arques (Newcastle University)H-Index: 2
Last. Andrew D. Rowan (Newcastle University)H-Index: 56
view all 4 authors...
: Cartilage destruction is a key characteristic of arthritic disease, a process now widely established to be mediated by metzincins such as MMPs. Despite showing promise in preclinical trials during the 1990s, MMP inhibitors for the blockade of extracellular matrix turnover in the treatment of cancer and arthritis failed clinically, primarily due to poor selectivity for target MMPs. In recent years, roles for serine proteinases in the proteolytic cascades leading to cartilage destruction have be...
13 CitationsSource
Cited By1
Newest
Source
Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders -...
1 CitationsSource