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Anabolic role of lysyl oxidase like-2 in cartilage of knee and temporomandibular joints with osteoarthritis

  • Alshenibr, Weam1
  • Tashkandi, Mustafa M.1
  • Alsaqer, Saqer F.1
  • Alkheriji, Yazeed1
  • Wise, Amelia2
  • Fulzele, Sadanand3
  • Mehra, Pushkar4
  • Goldring, Mary B.5, 6
  • Gerstenfeld, Louis C.2
  • Bais, Manish V.1
  • 1 Boston University Henry M. Goldman School of Dental Medicine, Department of Molecular and Cell Biology, W-216, 700 Albany Street, Boston, MA, 02118, USA , Boston (United States)
  • 2 Boston University, Department of Orthopaedic Surgery, School of Medicine, Boston, MA, 02118, USA , Boston (United States)
  • 3 Georgia Regents University, Department of Orthopaedic Surgery and Institute of Regenerative and Reparative Medicine, Augusta, GA, 30912, USA , Augusta (United States)
  • 4 Boston University Henry M. Goldman School of Dental Medicine, Department of Oral and Maxillofacial Surgery, 100 East Newton Street, Boston, MA, 02118, USA , Boston (United States)
  • 5 Weill Cornell Medical College, Hospital for Special Surgery Research Institute, New York, NY, 10021, USA , New York (United States)
  • 6 Weill Cornell Medical College, Department of Cell and Developmental Biology, New York, NY, 10021, USA , New York (United States)
Published Article
Arthritis Research & Therapy
Springer Science and Business Media LLC
Publication Date
Aug 02, 2017
DOI: 10.1186/s13075-017-1388-8
Springer Nature


BackgroundLysyl oxidase like-2 (LOXL2) is a copper-dependent amine oxidase. Our previous studies showed that LOXL2 is elevated during mouse fracture healing. The goal of this study was to evaluate the potential of LOXL2 to act as an anabolic agent in cartilage affected by osteoarthritis (OA).MethodsLOXL2 was visualized in tissues from human knee and hip joints and temporomandibular joints (TMJ) by immunofluorescence. The activity of LOXL2 in human articular and TMJ chondrocytes was assessed by cell-based assays, microarray analysis, and RT-qPCR, and LOXL2-mediated activation of NF-κB and extracellular signal-related kinase (ERK) signaling pathways was measured by western blotting. To examine LOXL2-induced effect in vivo, we implanted Matrigel-imbedded human chondrocytes into nude mice and exposed them to exogenous LOXL2 for 6 weeks. Finally, LOXL2-induced effects on collagen type 2 α1 (COL2A1) and phospho-SMAD2/3 were evaluated by immunofluorescence analysis.ResultsLOXL2 staining was detected in damaged regions of human TMJ, hip and knee joints affected by OA. Stimulation with transforming growth factor (TGF)-β1 upregulated LOXL2 expression, while pro-inflammatory cytokines IL-1β and TNF-α downregulated LOXL2, in human chondrocytes. Viral transduction of LOXL2 in OA chondrocytes increased the mRNA levels of chondroitin sulfate proteoglycan (CSPG4), aggrecan (ACAN), sex determining region Y-box containing gene 9 (SOX9), and COL2A1 but reduced the levels of extracellular matrix (ECM)-degrading enzymes matrix metalloproteinase (MMP)1, MMP3, and MMP13. Further, forced expression of LOXL2 promoted chondrogenic lineage-specific gene expression, increased the expression of COL2A1 in the presence of TNF-α, and inhibited chondrocyte apoptosis. LOXL2 expression also inhibited IL-1β-induced phospho-NF-κB/p65 and TGF-β1-induced ERK1/2 phosphorylation. Matrigel constructs of human chondrocytes from the knee joint and TMJ implanted in nude mice showed anabolic responses after LOXL2 transduction, including increased expression of SOX9, ACAN, and COL2A1. Finally, immunofluorescence staining revealed co-localization of LOXL2 with SOX9 in the nuclei of cells in the implants, decreased phospho-SMAD2/3, and increased COL2A1 staining.ConclusionOur results suggest that although LOXL2 is upregulated in cartilage affected by OA, this may be a protective response that promotes anabolism while inhibiting specific catabolic responses in the pathophysiology of OA.

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