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Open AccessArticle

Lysyl Oxidase-Like 2 Protects against Progressive and Aging Related Knee Joint Osteoarthritis in Mice

1
Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA
2
Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA
3
Departamento de Bioquímica, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, IdiPAZ, 28029 Madrid, Spain
4
Centro de Investigación Biomédica en Red Cáncer. Av Monforte de Lemos, 3-5, Pabellón 11, planta 0, 28029 Madrid, Spain
5
Department of Orthopedic Surgery, School of Medicine, Boston University, Boston, MA 02118, USA
6
Hospital for Special Surgery Research Institute, and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10021, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo km. 2. Majadahonda, 28220 Madrid, Spain.
Int. J. Mol. Sci. 2019, 20(19), 4798; https://doi.org/10.3390/ijms20194798
Received: 12 August 2019 / Revised: 12 September 2019 / Accepted: 26 September 2019 / Published: 27 September 2019
(This article belongs to the Special Issue The Future of Cartilage Repair in Complex Biological Situations)
Background: The goal of this study was to determine if adenovirus-delivered LOXL2 protects against progressive knee osteoarthritis (OA), assess its specific mechanism of action; and determine if the overexpression of LOXL2 in transgenic mice can protect against the development of OA-related cartilage damage and joint disability. Methods: Four-month-old Cho/+ male and female mice were intraperitoneally injected with either Adv-RFP-LOXL2 or an empty vector twice a month for four months. The proteoglycan levels and the expression of anabolic and catabolic genes were examined by immunostaining and qRT-PCR. The effect of LOXL2 expression on signaling was tested via the pro-inflammatory cytokine IL1β in the cartilage cell line ATDC5. Finally; the OA by monosodium iodoacetate (MIA) injection was also induced in transgenic mice with systemic overexpression of LOXL2 and examined gene expression and joint function by treadmill tests and assessment of allodynia. Results: The adenovirus treatment upregulated LOXL2; Sox9; Acan and Runx2 expression in both males and females. The Adv-RFP-LOXL2 injection; but not the empty vector injection increased proteoglycan staining and aggrecan expression but reduced MMP13 expression. LOXL2 attenuated IL-1β-induced phospho-NF-κB/p65 and rescued chondrogenic lineage-related genes in ATDC5 cells; demonstrating one potential protective mechanism. LOXL2 attenuated phospho-NF-κB independent of its enzymatic activity. Finally; LOXL2-overexpressing transgenic mice were protected from MIA-induced OA-related functional changes; including the time and distance traveled on the treadmill and allodynia. Conclusion: Our study demonstrates that systemic LOXL2 adenovirus or LOXL2 genetic overexpression in mice can protect against OA. These findings demonstrate the potential for LOXL2 gene therapy for knee-OA clinical treatment in the future. View Full-Text
Keywords: Lysyl oxidase like-2; adenovirus delivery; knee joint; articular cartilage; regeneration; osteoarthritis; anabolic response Lysyl oxidase like-2; adenovirus delivery; knee joint; articular cartilage; regeneration; osteoarthritis; anabolic response
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Tashkandi, M.; Ali, F.; Alsaqer, S.; Alhousami, T.; Cano, A.; Martin, A.; Salvador, F.; Portillo, F.; C. Gerstenfeld, L.; Goldring, M.B.; Bais, M.V. Lysyl Oxidase-Like 2 Protects against Progressive and Aging Related Knee Joint Osteoarthritis in Mice. Int. J. Mol. Sci. 2019, 20, 4798.

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