Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification
Lysyl oxidases (LOX(L)) are enzymes that catalyze the formation of cross-links in collagen and elastin fibers during physiologic calcification of bone. However, it remains unknown whether they may promote pathologic calcification of articular cartilage, an important hallmark of debilitating arthropa...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223018735 |
| _version_ | 1797324413467623424 |
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| author | Ilaria Bernabei Elodie Faure Mario Romani Julien Wegrzyn Jürgen Brinckmann Véronique Chobaz Alexander So Thomas Hugle Nathalie Busso Sonia Nasi |
| author_facet | Ilaria Bernabei Elodie Faure Mario Romani Julien Wegrzyn Jürgen Brinckmann Véronique Chobaz Alexander So Thomas Hugle Nathalie Busso Sonia Nasi |
| author_sort | Ilaria Bernabei |
| collection | DOAJ |
| description | Lysyl oxidases (LOX(L)) are enzymes that catalyze the formation of cross-links in collagen and elastin fibers during physiologic calcification of bone. However, it remains unknown whether they may promote pathologic calcification of articular cartilage, an important hallmark of debilitating arthropathies. Here, we have studied the possible roles of LOX(L) in cartilage calcification, related and not related to their cross-linking activity. We first demonstrated that inhibition of LOX(L) by β-aminoproprionitrile (BAPN) significantly reduced calcification in murine and human chondrocytes, and in joint of meniscectomized mice. These BAPN’s effects on calcification were accounted for by different LOX(L) roles. Firstly, reduced LOX(L)-mediated extracellular matrix cross-links downregulated Anx5, Pit1 and Pit2 calcification genes. Secondly, BAPN reduced collagen fibrotic markers Col1 and Col3. Additionally, LOX(L) inhibition blocked chondrocytes hypertrophic differentiation (Runx2 and COL10), pro-inflammatory IL-6 release and reactive oxygen species (ROS) production, all triggers of chondrocyte calcification. Through unbiased transcriptomic analysis we confirmed a positive correlation between LOX(L) genes and genes for calcification, hypertrophy and extracellular matrix catabolism. This association was conserved throughout species (mouse, human) and tissues that can undergo pathologic calcification (kidney, arteries, skin). Overall, LOX(L) play a critical role in the process of chondrocyte calcification and may be therapeutic targets to treat cartilage calcification in arthropathies. |
| first_indexed | 2024-03-08T05:55:48Z |
| format | Article |
| id | doaj.art-95beb48bdb064ce5b274060259551e7b |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-08T05:55:48Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-95beb48bdb064ce5b274060259551e7b2024-02-05T04:30:59ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-02-01171116075Inhibiting Lysyl Oxidases prevents pathologic cartilage calcificationIlaria Bernabei0Elodie Faure1Mario Romani2Julien Wegrzyn3Jürgen Brinckmann4Véronique Chobaz5Alexander So6Thomas Hugle7Nathalie Busso8Sonia Nasi9Service of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, SwitzerlandService of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, SwitzerlandAging and Bone Metabolism Laboratory, Service of Geriatric Medicine & Geriatric Rehabilitation, Department of Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, SwitzerlandDepartment of Orthopedic Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandDepartment of Dermatology and Institute of Virology and Cell Biology, University of Lübeck, Lübeck, GermanyService of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, SwitzerlandService of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, SwitzerlandService of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, SwitzerlandService of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, SwitzerlandService of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne; Lausanne, Switzerland; Correspondence to: Chemin des Boveressess, 155 1066 Epalinges, Switzerland.Lysyl oxidases (LOX(L)) are enzymes that catalyze the formation of cross-links in collagen and elastin fibers during physiologic calcification of bone. However, it remains unknown whether they may promote pathologic calcification of articular cartilage, an important hallmark of debilitating arthropathies. Here, we have studied the possible roles of LOX(L) in cartilage calcification, related and not related to their cross-linking activity. We first demonstrated that inhibition of LOX(L) by β-aminoproprionitrile (BAPN) significantly reduced calcification in murine and human chondrocytes, and in joint of meniscectomized mice. These BAPN’s effects on calcification were accounted for by different LOX(L) roles. Firstly, reduced LOX(L)-mediated extracellular matrix cross-links downregulated Anx5, Pit1 and Pit2 calcification genes. Secondly, BAPN reduced collagen fibrotic markers Col1 and Col3. Additionally, LOX(L) inhibition blocked chondrocytes hypertrophic differentiation (Runx2 and COL10), pro-inflammatory IL-6 release and reactive oxygen species (ROS) production, all triggers of chondrocyte calcification. Through unbiased transcriptomic analysis we confirmed a positive correlation between LOX(L) genes and genes for calcification, hypertrophy and extracellular matrix catabolism. This association was conserved throughout species (mouse, human) and tissues that can undergo pathologic calcification (kidney, arteries, skin). Overall, LOX(L) play a critical role in the process of chondrocyte calcification and may be therapeutic targets to treat cartilage calcification in arthropathies.http://www.sciencedirect.com/science/article/pii/S0753332223018735CartilageMicePathologic calcificationArthropathiesLysyl oxidases |
| spellingShingle | Ilaria Bernabei Elodie Faure Mario Romani Julien Wegrzyn Jürgen Brinckmann Véronique Chobaz Alexander So Thomas Hugle Nathalie Busso Sonia Nasi Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification Biomedicine & Pharmacotherapy Cartilage Mice Pathologic calcification Arthropathies Lysyl oxidases |
| title | Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification |
| title_full | Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification |
| title_fullStr | Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification |
| title_full_unstemmed | Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification |
| title_short | Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification |
| title_sort | inhibiting lysyl oxidases prevents pathologic cartilage calcification |
| topic | Cartilage Mice Pathologic calcification Arthropathies Lysyl oxidases |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223018735 |
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