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Malcolm Collins - One of the best experts on this subject based on the ideXlab platform.
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matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament acl rupture
Scandinavian Journal of Medicine & Science in Sports, 2012Co-Authors: Michael Posthumus, Malcolm Collins, L Van Der Merwe, D Ocuinneagain, W Van Der Merwe, William J RibbansAbstract:Abstract As matrix metalloproteinases (MMPs) are critical to ligament homeostasis and integrity, the aim of this study was to investigate whether four functional polymorphisms within four MMP genes, which cluster on chromosome 11q22 associate with risk of ACL ruptures. Three hundred and forty-five [129 with ACL ruptures (ACL group) and 216 asymptomatic controls (CON group)] unrelated Caucasians were recruited for this case-control study. Fifty-four participants reported non-contact mechanisms of ACL rupture (NON subgroup). All participants were genotyped for the MMP10 C/T rs486055, MMP1 1G/2G rs1799750, MMP3 G/A rs679620 and MMP12 A/G rs2276109 variants. After adjusting for sex, age and weight, the AG and GG genotypes of the MMP12 rs2276109 variant were significantly (P=0.030) under-represented among the NON subgroup (14%), when compared with the CON group (26%). No other variants were significantly different between groups. Adjusted for the same confounders, the two four-variant haplotypes T-1G-A-A (CON 14%, ACL 9%, P=0.033) and C-2G-G-G (CON 14%, NON 5%, P=0.021) were significantly different between the CON and the ACL groups, and the CON group and the NON subgroup, respectively. This is the first report that indicates an association between the chromosomal region 11q22 and the risk of ACL rupture.
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matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament acl rupture
British Journal of Sports Medicine, 2011Co-Authors: Michael Posthumus, Malcolm Collins, L Van Der Merwe, D Ocuinneagain, W Van Der Merwe, William J RibbansAbstract:Background Anterior cruciate ligament (ACL) rupture is a complex disorder for which several risk factors, including genetic factors, have been established. Objective As matrix metalloproteinases (MMPs) are critical to ligament homeostasis and integrity, the primary aim of this study was to investigate if four selected polymorphisms within four MMP genes, which cluster on chromosome 11q22, associate with risk of ACL ruptures. Methods 343 (138 individuals with ACL ruptures (ACL group) and 215 asymptomatic controls (CON group)) unrelated Caucasians were recruited for this case-control genetic association study. The ACL group included 54 participants with a non-contact mechanism of ACL rupture (NON- subgroup). All participants were genotyped using fluorescence-based assays, for the four selected functional polymorphisms; namely the MMP10 C/T rs486055, MMP1 1G/2G rs1799750, MMP3 G/A rs679620 and MMP12 A/G rs2276109 variants. Results When adjusted for sex, age and weight, the AG and GG genotypes of the MMP12 rs2276109 variant were significantly (p=0.030) under-represented among the NON-subgroups (14%), when compared to the CON group (26%). No other variants were significantly different between groups. In addition, when adjusted for the same confounders, the four variant haplotypes T-1G-A-A (CON 14%, ACL 9%, p=0.033) and C-2G-G-G (CON 14%, NON 5%, p=0.021) were significantly different between the CON group and the ACL group, as well as the CON and NON sub-group, respectively. Conclusion This study reports for the first time that the chromosomal region 11q22 is associated with risk of ACL rupture. The genetic risk profile reported in this study, together with genetic risk factors previously associated, and those yet to be identified, should in the future be included in multifactorial models designed to reduce the incidence of ACL rupture within ‘at-risk’ populations. Further research is required to replicate these findings in an independent population.
L Van Der Merwe - One of the best experts on this subject based on the ideXlab platform.
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matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament acl rupture
Scandinavian Journal of Medicine & Science in Sports, 2012Co-Authors: Michael Posthumus, Malcolm Collins, L Van Der Merwe, D Ocuinneagain, W Van Der Merwe, William J RibbansAbstract:Abstract As matrix metalloproteinases (MMPs) are critical to ligament homeostasis and integrity, the aim of this study was to investigate whether four functional polymorphisms within four MMP genes, which cluster on chromosome 11q22 associate with risk of ACL ruptures. Three hundred and forty-five [129 with ACL ruptures (ACL group) and 216 asymptomatic controls (CON group)] unrelated Caucasians were recruited for this case-control study. Fifty-four participants reported non-contact mechanisms of ACL rupture (NON subgroup). All participants were genotyped for the MMP10 C/T rs486055, MMP1 1G/2G rs1799750, MMP3 G/A rs679620 and MMP12 A/G rs2276109 variants. After adjusting for sex, age and weight, the AG and GG genotypes of the MMP12 rs2276109 variant were significantly (P=0.030) under-represented among the NON subgroup (14%), when compared with the CON group (26%). No other variants were significantly different between groups. Adjusted for the same confounders, the two four-variant haplotypes T-1G-A-A (CON 14%, ACL 9%, P=0.033) and C-2G-G-G (CON 14%, NON 5%, P=0.021) were significantly different between the CON and the ACL groups, and the CON group and the NON subgroup, respectively. This is the first report that indicates an association between the chromosomal region 11q22 and the risk of ACL rupture.
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matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament acl rupture
British Journal of Sports Medicine, 2011Co-Authors: Michael Posthumus, Malcolm Collins, L Van Der Merwe, D Ocuinneagain, W Van Der Merwe, William J RibbansAbstract:Background Anterior cruciate ligament (ACL) rupture is a complex disorder for which several risk factors, including genetic factors, have been established. Objective As matrix metalloproteinases (MMPs) are critical to ligament homeostasis and integrity, the primary aim of this study was to investigate if four selected polymorphisms within four MMP genes, which cluster on chromosome 11q22, associate with risk of ACL ruptures. Methods 343 (138 individuals with ACL ruptures (ACL group) and 215 asymptomatic controls (CON group)) unrelated Caucasians were recruited for this case-control genetic association study. The ACL group included 54 participants with a non-contact mechanism of ACL rupture (NON- subgroup). All participants were genotyped using fluorescence-based assays, for the four selected functional polymorphisms; namely the MMP10 C/T rs486055, MMP1 1G/2G rs1799750, MMP3 G/A rs679620 and MMP12 A/G rs2276109 variants. Results When adjusted for sex, age and weight, the AG and GG genotypes of the MMP12 rs2276109 variant were significantly (p=0.030) under-represented among the NON-subgroups (14%), when compared to the CON group (26%). No other variants were significantly different between groups. In addition, when adjusted for the same confounders, the four variant haplotypes T-1G-A-A (CON 14%, ACL 9%, p=0.033) and C-2G-G-G (CON 14%, NON 5%, p=0.021) were significantly different between the CON group and the ACL group, as well as the CON and NON sub-group, respectively. Conclusion This study reports for the first time that the chromosomal region 11q22 is associated with risk of ACL rupture. The genetic risk profile reported in this study, together with genetic risk factors previously associated, and those yet to be identified, should in the future be included in multifactorial models designed to reduce the incidence of ACL rupture within ‘at-risk’ populations. Further research is required to replicate these findings in an independent population.
Klaus Wielckens - One of the best experts on this subject based on the ideXlab platform.
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matrilin 3 activates the expression of osteoarthritis associated genes in primary human chondrocytes
FEBS Letters, 2009Co-Authors: Andreas R Klatt, Mats Paulsson, Raimund Wagener, Gabriele Klinger, Gertrud Kühn, Joerg H. Renno, Joachim Schmidt, Gebhart Malchau, Brigitte Paulklausch, Klaus WielckensAbstract:Here, we tested the matrilin-3-dependent induction of osteoarthritis-associated genes in primary human chondrocytes. Matrilin stimulation leads to the induction of MMP1, MMP3, MMP13, COX-2, iNOS, IL-1β, TNFα, IL-6 and IL-8. Furthermore, we show the participation of ADAMTS4 and ADAMTS5 in the in vitro degradation of matrilin-3. We provide evidence for a matrilin-3-dependent feed-forward mechanism of matrix degradation, whereby proteolytically-released matrilin-3 induces pro-inflammatory cytokines as well as ADAMTS4 and -5 indirectly via IL-1β. ADAMTS4 and ADAMTS5, in turn, cleave matrilin-3 and may release more matrilin-3 from the matrix, which could lead to further release of pro-inflammatory cytokines and proteases in cartilage.
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a critical role for collagen ii in cartilage matrix degradation collagen ii induces pro inflammatory cytokines and mmps in primary human chondrocytes
Journal of Orthopaedic Research, 2009Co-Authors: Andreas R Klatt, Gabriele Klinger, Joerg H. Renno, Gebhart Malchau, Brigitte Paulklausch, Getrud Kuhn, Marc Banerjee, Klaus WielckensAbstract:We report a process that results in the acceleration of matrix degradation in human articular cartilage, a phenomenon commonly observed in osteoarthritis (OA). The study was conducted by (1) examining the potential of collagen II in modulating the gene expression profile of primary human chondrocytes (PHCs), and (2) investigating the involvement of pro-inflammatory signaling cascades. We first tested the collagen II-dependent induction of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in PHCs. PHCs were incubated with or without monomeric (i.e., nonfibrillar) collagen II. Cells were then analyzed by RT-PCR for the expression of MMP1, MMP3, MMP13, MMP14, and IL-1β. ELISA was used to quantify IL-6 and IL-8 release. To examine the influence of collagen II signaling, specifically the role of MAPK p38, a p38-inhibitor was added prior to collagen treatment. Changes in IκB concentration were monitored by immunoblot analysis to detect NFκB signaling. Results indicated that incubation of PHCs with collagen II did produce a dose-dependent induction of MMP1, MMP3, MMP13, MMP14, as well as cytokines IL-1β, IL-6, and IL-8. At the same time, inhibition of p38 and IκB degradation revealed that collagen II-dependent gene induction also involves MAPK p38 and NFκB signaling. Thus, we provide evidence for a collagen II-dependent feed-forward mechanism whereby collagen II induces first MMPs and pro-inflammatory cytokines and then release of collagen II fragments from mature collagen II fibers. This, in turn, induces more pro-inflammatory cytokines and MMPs, and the process is repeated, which results in the acceleration and perpetuation of cartilage matrix degradation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:65–70, 2009
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a critical role for collagen ii in cartilage matrix degradation collagen ii induces pro inflammatory cytokines and mmps in primary human chondrocytes
Journal of Orthopaedic Research, 2009Co-Authors: Andreas R Klatt, Gabriele Klinger, Joerg H. Renno, Gebhart Malchau, Brigitte Paulklausch, Getrud Kuhn, Marc Banerjee, Klaus WielckensAbstract:We report a process that results in the acceleration of matrix degradation in human articular cartilage, a phenomenon commonly observed in osteoarthritis (OA). The study was conducted by (1) examining the potential of collagen II in modulating the gene expression profile of primary human chondrocytes (PHCs), and (2) investigating the involvement of pro-inflammatory signaling cascades. We first tested the collagen II-dependent induction of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in PHCs. PHCs were incubated with or without monomeric (i.e., nonfibrillar) collagen II. Cells were then analyzed by RT-PCR for the expression of MMP1, MMP3, MMP13, MMP14, and IL-1beta. ELISA was used to quantify IL-6 and IL-8 release. To examine the influence of collagen II signaling, specifically the role of MAPK p38, a p38-inhibitor was added prior to collagen treatment. Changes in IkappaB concentration were monitored by immunoblot analysis to detect NFkappaB signaling. Results indicated that incubation of PHCs with collagen II did produce a dose-dependent induction of MMP1, MMP3, MMP13, MMP14, as well as cytokines IL-1beta, IL-6, and IL-8. At the same time, inhibition of p38 and IkappaB degradation revealed that collagen II-dependent gene induction also involves MAPK p38 and NFkappaB signaling. Thus, we provide evidence for a collagen II-dependent feed-forward mechanism whereby collagen II induces first MMPs and pro-inflammatory cytokines and then release of collagen II fragments from mature collagen II fibers. This, in turn, induces more pro-inflammatory cytokines and MMPs, and the process is repeated, which results in the acceleration and perpetuation of cartilage matrix degradation.
William J Ribbans - One of the best experts on this subject based on the ideXlab platform.
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matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament acl rupture
Scandinavian Journal of Medicine & Science in Sports, 2012Co-Authors: Michael Posthumus, Malcolm Collins, L Van Der Merwe, D Ocuinneagain, W Van Der Merwe, William J RibbansAbstract:Abstract As matrix metalloproteinases (MMPs) are critical to ligament homeostasis and integrity, the aim of this study was to investigate whether four functional polymorphisms within four MMP genes, which cluster on chromosome 11q22 associate with risk of ACL ruptures. Three hundred and forty-five [129 with ACL ruptures (ACL group) and 216 asymptomatic controls (CON group)] unrelated Caucasians were recruited for this case-control study. Fifty-four participants reported non-contact mechanisms of ACL rupture (NON subgroup). All participants were genotyped for the MMP10 C/T rs486055, MMP1 1G/2G rs1799750, MMP3 G/A rs679620 and MMP12 A/G rs2276109 variants. After adjusting for sex, age and weight, the AG and GG genotypes of the MMP12 rs2276109 variant were significantly (P=0.030) under-represented among the NON subgroup (14%), when compared with the CON group (26%). No other variants were significantly different between groups. Adjusted for the same confounders, the two four-variant haplotypes T-1G-A-A (CON 14%, ACL 9%, P=0.033) and C-2G-G-G (CON 14%, NON 5%, P=0.021) were significantly different between the CON and the ACL groups, and the CON group and the NON subgroup, respectively. This is the first report that indicates an association between the chromosomal region 11q22 and the risk of ACL rupture.
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matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament acl rupture
British Journal of Sports Medicine, 2011Co-Authors: Michael Posthumus, Malcolm Collins, L Van Der Merwe, D Ocuinneagain, W Van Der Merwe, William J RibbansAbstract:Background Anterior cruciate ligament (ACL) rupture is a complex disorder for which several risk factors, including genetic factors, have been established. Objective As matrix metalloproteinases (MMPs) are critical to ligament homeostasis and integrity, the primary aim of this study was to investigate if four selected polymorphisms within four MMP genes, which cluster on chromosome 11q22, associate with risk of ACL ruptures. Methods 343 (138 individuals with ACL ruptures (ACL group) and 215 asymptomatic controls (CON group)) unrelated Caucasians were recruited for this case-control genetic association study. The ACL group included 54 participants with a non-contact mechanism of ACL rupture (NON- subgroup). All participants were genotyped using fluorescence-based assays, for the four selected functional polymorphisms; namely the MMP10 C/T rs486055, MMP1 1G/2G rs1799750, MMP3 G/A rs679620 and MMP12 A/G rs2276109 variants. Results When adjusted for sex, age and weight, the AG and GG genotypes of the MMP12 rs2276109 variant were significantly (p=0.030) under-represented among the NON-subgroups (14%), when compared to the CON group (26%). No other variants were significantly different between groups. In addition, when adjusted for the same confounders, the four variant haplotypes T-1G-A-A (CON 14%, ACL 9%, p=0.033) and C-2G-G-G (CON 14%, NON 5%, p=0.021) were significantly different between the CON group and the ACL group, as well as the CON and NON sub-group, respectively. Conclusion This study reports for the first time that the chromosomal region 11q22 is associated with risk of ACL rupture. The genetic risk profile reported in this study, together with genetic risk factors previously associated, and those yet to be identified, should in the future be included in multifactorial models designed to reduce the incidence of ACL rupture within ‘at-risk’ populations. Further research is required to replicate these findings in an independent population.
Andreas R Klatt - One of the best experts on this subject based on the ideXlab platform.
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matrilin 3 activates the expression of osteoarthritis associated genes in primary human chondrocytes
FEBS Letters, 2009Co-Authors: Andreas R Klatt, Mats Paulsson, Raimund Wagener, Gabriele Klinger, Gertrud Kühn, Joerg H. Renno, Joachim Schmidt, Gebhart Malchau, Brigitte Paulklausch, Klaus WielckensAbstract:Here, we tested the matrilin-3-dependent induction of osteoarthritis-associated genes in primary human chondrocytes. Matrilin stimulation leads to the induction of MMP1, MMP3, MMP13, COX-2, iNOS, IL-1β, TNFα, IL-6 and IL-8. Furthermore, we show the participation of ADAMTS4 and ADAMTS5 in the in vitro degradation of matrilin-3. We provide evidence for a matrilin-3-dependent feed-forward mechanism of matrix degradation, whereby proteolytically-released matrilin-3 induces pro-inflammatory cytokines as well as ADAMTS4 and -5 indirectly via IL-1β. ADAMTS4 and ADAMTS5, in turn, cleave matrilin-3 and may release more matrilin-3 from the matrix, which could lead to further release of pro-inflammatory cytokines and proteases in cartilage.
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a critical role for collagen ii in cartilage matrix degradation collagen ii induces pro inflammatory cytokines and mmps in primary human chondrocytes
Journal of Orthopaedic Research, 2009Co-Authors: Andreas R Klatt, Gabriele Klinger, Joerg H. Renno, Gebhart Malchau, Brigitte Paulklausch, Getrud Kuhn, Marc Banerjee, Klaus WielckensAbstract:We report a process that results in the acceleration of matrix degradation in human articular cartilage, a phenomenon commonly observed in osteoarthritis (OA). The study was conducted by (1) examining the potential of collagen II in modulating the gene expression profile of primary human chondrocytes (PHCs), and (2) investigating the involvement of pro-inflammatory signaling cascades. We first tested the collagen II-dependent induction of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in PHCs. PHCs were incubated with or without monomeric (i.e., nonfibrillar) collagen II. Cells were then analyzed by RT-PCR for the expression of MMP1, MMP3, MMP13, MMP14, and IL-1β. ELISA was used to quantify IL-6 and IL-8 release. To examine the influence of collagen II signaling, specifically the role of MAPK p38, a p38-inhibitor was added prior to collagen treatment. Changes in IκB concentration were monitored by immunoblot analysis to detect NFκB signaling. Results indicated that incubation of PHCs with collagen II did produce a dose-dependent induction of MMP1, MMP3, MMP13, MMP14, as well as cytokines IL-1β, IL-6, and IL-8. At the same time, inhibition of p38 and IκB degradation revealed that collagen II-dependent gene induction also involves MAPK p38 and NFκB signaling. Thus, we provide evidence for a collagen II-dependent feed-forward mechanism whereby collagen II induces first MMPs and pro-inflammatory cytokines and then release of collagen II fragments from mature collagen II fibers. This, in turn, induces more pro-inflammatory cytokines and MMPs, and the process is repeated, which results in the acceleration and perpetuation of cartilage matrix degradation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:65–70, 2009
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a critical role for collagen ii in cartilage matrix degradation collagen ii induces pro inflammatory cytokines and mmps in primary human chondrocytes
Journal of Orthopaedic Research, 2009Co-Authors: Andreas R Klatt, Gabriele Klinger, Joerg H. Renno, Gebhart Malchau, Brigitte Paulklausch, Getrud Kuhn, Marc Banerjee, Klaus WielckensAbstract:We report a process that results in the acceleration of matrix degradation in human articular cartilage, a phenomenon commonly observed in osteoarthritis (OA). The study was conducted by (1) examining the potential of collagen II in modulating the gene expression profile of primary human chondrocytes (PHCs), and (2) investigating the involvement of pro-inflammatory signaling cascades. We first tested the collagen II-dependent induction of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in PHCs. PHCs were incubated with or without monomeric (i.e., nonfibrillar) collagen II. Cells were then analyzed by RT-PCR for the expression of MMP1, MMP3, MMP13, MMP14, and IL-1beta. ELISA was used to quantify IL-6 and IL-8 release. To examine the influence of collagen II signaling, specifically the role of MAPK p38, a p38-inhibitor was added prior to collagen treatment. Changes in IkappaB concentration were monitored by immunoblot analysis to detect NFkappaB signaling. Results indicated that incubation of PHCs with collagen II did produce a dose-dependent induction of MMP1, MMP3, MMP13, MMP14, as well as cytokines IL-1beta, IL-6, and IL-8. At the same time, inhibition of p38 and IkappaB degradation revealed that collagen II-dependent gene induction also involves MAPK p38 and NFkappaB signaling. Thus, we provide evidence for a collagen II-dependent feed-forward mechanism whereby collagen II induces first MMPs and pro-inflammatory cytokines and then release of collagen II fragments from mature collagen II fibers. This, in turn, induces more pro-inflammatory cytokines and MMPs, and the process is repeated, which results in the acceleration and perpetuation of cartilage matrix degradation.
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tak1 downregulation reduces il 1β induced expression of mmp13 mmp1 and tnf alpha
Biomedicine & Pharmacotherapy, 2006Co-Authors: Andreas R Klatt, Gabriele Klinger, Olga Neumuller, Bernd Eidenmuller, Ingrid Wagner, Tatjana Achenbach, Thomas Aigner, Eckart BartnikAbstract:The paper provides evidence that transforming growth factor-beta activated kinase 1 (TAK1, MEKK7), a downstream mediator of IL-1beta signal transduction, plays an important role in the regulation of catabolic events and inflammatory processes in the context of degenerative joint diseases. We investigated the expression of TAK1 in human articular chondrocytes and in the murine growth plate by cDNA array, quantitative RT-PCR and immunohistochemistry, respectively. The human chondrosarcoma cell line SW1353 was stimulated with the proinflammatory cytokine IL-1beta. The subsequent expression of proteolytic enzymes and proinflammatory cytokines was quantified. TAK1 specific siRNA was used to study the influence of TAK1 downregulation on the expression of MMP-13, MMP1 and TNF-alpha. As a result we demonstrated the expression of TAK1 in normal and osteoarthritic human articular cartilage. Expression of TAK1 in the hypertrophic zone of the growth plate gave us a first evidence for a catabolic function of TAK1 concerning cartilage metabolism. By gene suppression with RNAi technology we could show that TAK1 downregulation leads to a 60-70% reduced release of TNF-alpha, a 40-50% reduced release of MMP13, and a 20-30% reduction of MMP1 release. As TNF-alpha is a main player in inflammatory processes, and MMP13 is one of the major proteases involved in cartilage degradation, our results suggests that TAK1 has an important regulatory role in the context of degenerative joint diseases and thus is an attractive drug target in attempts to reduce inflammation and suppress structural changes in OA induced by IL-1beta.