The contribution of ADAM12 and CILP genes to the development of knee osteoarthritis
Date
2014-04-22
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Abstract
Osteoartriit (OA) on kõige levinum liigesehaigus, mille kujunemisel on oluline roll nii väliskeskkonna faktoritel kui geneetilisel eelsoodumusel. On teada, et geenid võivad mõjutada OA kulgu ja raskust, samuti ka teisi OA riskifaktoreid. Tänapäeval käsitletakse OA kõiki liigesekudesid haarava protsessina, mille kujunemisel on oluline roll põletiku komponendil. Haiguse lai levik, definitiivse ravi puudumine ning lünklik arusaam protsessi patogeneesist tekitab vajaduse üksikasjalikult uurida kandidaatgeenide seoseid haigusega nii DNA, vastava valgu kui ka RNA tasemel. Selle uurimuse eesmärkideks oli selgitada põlve OA (POA) kahe kandidaatgeeni−ADAM12 (desintegriin ja metallopeptidaasi domään 12) ja CILP (kõhre keskmise kihi proteiin)−seotust POA patogeneesi teatud aspektidega. Mõlema geeni seost POA-ga on vähe uuritud ning puuduvad andmed Eesti populatsiooni kohta. Uurimus tugines populatsioonil baseeruv kohortile (N=437) ning artroskoopiliselt ravitud patsientidele (N=91) vanuses 32−60 a.
Uurimistöö käigus avastati ADAM12 seos POA riskiga geeni ja valgu tasemel. Leiti seos ADAM12 geeni polümorfismide ning radioloogilise POA-ga. POA riskiga seotud variandid erinesid meestel ja naistel. Radioloogilistest tunnustest määratles ADAM12 ainult ostefüütide tekke riski mõlemal sool. ADAM12 geeni valk-produkti ADAM12-S kontsentratsioon seerumis oli oluliselt kõrgem väljendunud radioloogilise POA-ga isikutel. Leiti korrelatsioon ADAM12 mRNA sünoviaalse ekspressiooni ja sünoviidi vahel, tugevaim seos sünoviidi tunnustest esines fibroosiga.
Kõhre-spetsiifiliseks peetavat markerit CILP-i leiti sünoovias mRNA ja valgu tasemel, mis osutab võimalusele, et sünoviaalmembraan võib olla täiendavaks CILP produktsiooni allikaks. Sarnaselt ADAM12-ga leiti CILP mRNA üleekspressioon fibrootilistes proovides. CILP mRNA sünoviaalne ekspressioon oli oluliselt madalam neil isikutel, kel oli väljendunud liigespilu kitsenemine. Mõlemad geenid avaldusid soo-spetsifilist mõju varajase ja hilise radioloogilise POA riskile ning fibrogeneesile.
Käesolev uuring näitab ADAM12 ja CILP geenide seost OA patogeneesi erinevate aspektidega−ADAM12 geeni osalemist luu remodeleerimise protsessides (osteofüütide teke) ning ADAM12 ja CILP geenide osalemist sünoviaalse fibroosi arenemisel.
Osteoarthritis (OA) is the most common arthritic disorder, with a large number of environmental and genetic risk factors. Genetic factors have been shown to influence the dynamics and outcomes of OA, as have other OA risk factors. Currently, OA is recognised as a form of arthritis with an inflammatory component, which involves all of the joint tissues. The global burden of the disease and lack of definitive treatment, as well insufficient knowledge of several pathogenetic steps, ensure the importance of genetic research in OA. Comprehensive consideration of promising candidate genes on the mRNA and protein levels could improve our current knowledge of the disease. The aims of the present study were to perform an analysis of two OA candidate genes–ADAM12 (disintegrin and metalloproteinase domain 12) and CILP (cartilage intermediate layer protein)–on DNA-RNA-protein levels in radiographic knee OA (rKOA). The study consisted of a population-based cohort (N=437) and subjects undergoing arthroscopy (N=91), aged 32–60. The current study demonstrated that ADAM12 is associated with rKOA processes at different levels (gene and protein). Polymorphisms of the ADAM12 gene carried the risk of rKOA. In males and females rKOA risk was associated with different variants. In both genders the risk was associated only with osteophytosis. The protein product of the ADAM12 gene (ADAM12-S) was found at higher concentrations in the late stages of the disease. The expression of ADAM12 mRNA and protein in synovia was up-regulated during synovial inflammation, especially in fibrosis. CILP, which is thought to be a specific cartilage biomarker, was found in synovia at the mRNA and protein levels, suggesting that synovia may be an additional source of CILP production. Similarly to ADAM12, the synovial expression of CILP mRNA was found to be up-regulated in fibrotic samples. Moreover, CILP mRNA expression was down-regulated in subjects with advanced stages of joint space narrowing. Both genes demonstrated gender-specific effects on rKOA risk and synovial fibrogenesis. The present study establishes the association of ADAM12 and CILP genes with different aspects of KOA pathogenesis, suggesting involvement of the ADAM12 gene in bone remodelling (osteophytosis), as well the role of ADAM12 and CILP genes in the development of synovial fibrosis.
Osteoarthritis (OA) is the most common arthritic disorder, with a large number of environmental and genetic risk factors. Genetic factors have been shown to influence the dynamics and outcomes of OA, as have other OA risk factors. Currently, OA is recognised as a form of arthritis with an inflammatory component, which involves all of the joint tissues. The global burden of the disease and lack of definitive treatment, as well insufficient knowledge of several pathogenetic steps, ensure the importance of genetic research in OA. Comprehensive consideration of promising candidate genes on the mRNA and protein levels could improve our current knowledge of the disease. The aims of the present study were to perform an analysis of two OA candidate genes–ADAM12 (disintegrin and metalloproteinase domain 12) and CILP (cartilage intermediate layer protein)–on DNA-RNA-protein levels in radiographic knee OA (rKOA). The study consisted of a population-based cohort (N=437) and subjects undergoing arthroscopy (N=91), aged 32–60. The current study demonstrated that ADAM12 is associated with rKOA processes at different levels (gene and protein). Polymorphisms of the ADAM12 gene carried the risk of rKOA. In males and females rKOA risk was associated with different variants. In both genders the risk was associated only with osteophytosis. The protein product of the ADAM12 gene (ADAM12-S) was found at higher concentrations in the late stages of the disease. The expression of ADAM12 mRNA and protein in synovia was up-regulated during synovial inflammation, especially in fibrosis. CILP, which is thought to be a specific cartilage biomarker, was found in synovia at the mRNA and protein levels, suggesting that synovia may be an additional source of CILP production. Similarly to ADAM12, the synovial expression of CILP mRNA was found to be up-regulated in fibrotic samples. Moreover, CILP mRNA expression was down-regulated in subjects with advanced stages of joint space narrowing. Both genes demonstrated gender-specific effects on rKOA risk and synovial fibrogenesis. The present study establishes the association of ADAM12 and CILP genes with different aspects of KOA pathogenesis, suggesting involvement of the ADAM12 gene in bone remodelling (osteophytosis), as well the role of ADAM12 and CILP genes in the development of synovial fibrosis.
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Keywords
põlveliiges, osteoartroos, geenid, populatsioonigeneetika, Eesti, knee joint, osteoarthritis, genes, population genetics, Estonia