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      Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis

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          Abstract

          Osteoarthritis (OA) is an extremely prevalent age-related condition. The economic and societal burden due to the cost of symptomatic treatment, inability to work, joint replacement, and rehabilitation is huge and increasing. Currently, there are no effective medical therapies that delay or reverse the pathological manifestations of OA. Current treatment options are, without exception, focused on slowing down progression of the disease to postpone total joint replacement surgery for as long as possible and keeping the associated pain and joint immobility manageable. Alterations in the articular cartilage chondrocyte phenotype might be fundamental in the pathological mechanisms of OA development. In many ways, the changing chondrocyte phenotype in osteoarthritic cartilage resembles the process of endochondral ossification as seen, for instance, in developing growth plates. However, the relative contribution of endochondral ossification to the changing chondrocyte phenotype in the development and progression of OA remains poorly described. In this review, we will discuss the current knowledge regarding the cartilage endochondral phenotypic changes occurring during OA development and progression, as well as the molecular and environmental effectors driving these changes. Understanding how these molecular mechanisms determine the chondrocyte cell fate in OA will be essential in enabling cartilage regenerative approaches in future treatments of OA.

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          Most cited references105

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          Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis.

          During osteoarthritis (OA), angiogenesis is increased in the synovium, osteophytes and menisci and leads to ossification in osteophytes and the deep layers of articular cartilage. Angiogenic and antiangiogenic factors might both be upregulated in the osteoarthritic joint; however, vascular growth predominates, and the articular cartilage loses its resistance to vascularization. In addition, blood vessel growth is increased at--and disrupts--the osteochondral junction. Angiogenesis in this location is dependent on the creation of channels from subchondral bone spaces into noncalcified articular cartilage. Inflammation drives synovial angiogenesis through macrophage activation. Blood vessel and nerve growth are linked by common pathways that involve the release of proangiogenic factors, such as vascular endothelial growth factor, β-nerve growth factor and neuropeptides. Proangiogenic factors might also stimulate nerve growth, and molecules produced by vascular cells could both stimulate and guide nerve growth. As sensory nerves grow along new blood vessels in osteoarthritic joints, they eventually penetrate noncalcified articular cartilage, osteophytes and the inner regions of menisci. Angiogenesis could, therefore, contribute to structural damage and pain in OA and provide potential targets for new treatments.
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            Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.

            Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.
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              Mitogen-activated protein kinases: specific messages from ubiquitous messengers.

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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/509097
                URI : http://frontiersin.org/people/u/530675
                URI : http://frontiersin.org/people/u/530634
                URI : http://frontiersin.org/people/u/413903
                Journal
                Front Bioeng Biotechnol
                Front Bioeng Biotechnol
                Front. Bioeng. Biotechnol.
                Frontiers in Bioengineering and Biotechnology
                Frontiers Media S.A.
                2296-4185
                19 March 2018
                2018
                : 6
                : 18
                Affiliations
                [1] 1Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University Medical Center , Maastricht, Netherlands
                Author notes

                Edited by: Eric Farrell, Erasmus University Rotterdam, Netherlands

                Reviewed by: Katherine A. Staines, Edinburgh Napier University, United Kingdom; Andrea Lolli, Erasmus Medical Center, Erasmus University Rotterdam, Netherlands

                *Correspondence: Tim J. M. Welting, t.welting@ 123456maastrichtuniversity.nl

                Co-first authors.

                Co-last authors.

                Specialty section: This article was submitted to Tissue Engineering and Regenerative Medicine, a section of the journal Frontiers in Bioengineering and Biotechnology

                Article
                10.3389/fbioe.2018.00018
                5867295
                29616218
                b8c2c719-daa0-49ee-ba98-f9fec586d061
                Copyright © 2018 Ripmeester, Timur, Caron and Welting.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 December 2017
                : 08 February 2018
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 128, Pages: 25, Words: 19461
                Funding
                Funded by: Reumafonds 10.13039/501100006315
                Award ID: LLP14, 15-3-403
                Funded by: Stichting Sint Annadal 10.13039/501100004529
                Categories
                Bioengineering and Biotechnology
                Review

                chondrocytes,osteoarthritis,hypertrophy,cartilage,phenotype,endochondral ossification

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