Lysyl Oxidase-Like 2 Protects against Progressive and Aging Related Knee Joint Osteoarthritis in Mice
Abstract
:1. Introduction
2. Results
2.1. Adenoviral LOXL2 Protects Against Progressive OA in Cho/+ Mice
2.2. LOXL2 Attenuates IL-1β Induced NF-κB in Cartilage
2.3. Enzymatically Inactive LOXL2 also Attenuates IL-1β-Induced NF-κB Activity
2.4. LOXL2 Overexpression Protects Against Catabolic Changes in Aging Knee OA
2.5. Overexpression of LOXL2 Protects Against Functional Changes in Aging Knee OA
3. Discussion
4. Materials and Methods
4.1. Animal Experiments
4.2. Preparation of Adenovirus
4.3. Cho/+ Mouse Experiments
4.4. Cytotoxicity and Immune Effect of Adenovirus Vector
4.5. RNA Isolation and Analysis
4.6. Histology and Immunostaining
4.7. MIA Mouse Model and Treadmill Running in Aging Mice
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Losina, E.; Weinstein, A.M.; Reichmann, W.M.; Burbine, S.A.; Solomon, D.H.; Daigle, M.E.; Rome, B.N.; Chen, S.P.; Hunter, D.J.; Suter, L.G.; et al. Lifetime risk and age at diagnosis of symptomatic knee osteoarthritis in the US. Arthritis Care Res. 2013, 65, 703–711. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Iversen, M.D.; McAlindon, T.; Harvey, W.F.; Wong, J.B.; Fielding, R.A.; Driban, J.B.; Price, L.L.; Rones, R.; Gamache, T.; et al. Assessing the comparative effectiveness of Tai Chi versus physical therapy for knee osteoarthritis: Design and rationale for a randomized trial. BMC Complement. Altern. Med. 2014, 14, 333. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, U.S.; Zhang, Y.; Zhu, Y.; Niu, J.; Zhang, B.; Felson, D.T. Increasing prevalence of knee pain and symptomatic knee osteoarthritis: Survey and cohort data. Ann. Intern. Med. 2011, 155, 725–732. [Google Scholar] [CrossRef] [PubMed]
- Bais, M.; McLean, J.; Sebastiani, P.; Young, M.; Wigner, N.; Smith, T.; Kotton, D.N.; Einhorn, T.A.; Einhorn, T.A.; Gerstenfeld, L.C. Transcriptional analysis of fracture healing and the induction of embryonic stem cell-related genes. PLoS ONE 2009, 4, e5393. [Google Scholar] [CrossRef] [PubMed]
- Iftikhar, M.; Hurtado, P.; Bais, M.V.; Wigner, N.; Stephens, D.N.; Gerstnefeld, L.C.; Trackman, P.C. Lysyl oxidase-like-2 (LOXL2) is a major isoform in chondrocytes and is critically required for differentiation. Biochem. J. Biol. Chem. 2011, 286, 909–918. [Google Scholar] [CrossRef] [PubMed]
- Alshenibr, W.; Tashkandi, M.M.; Alsaqer, S.F.; Alkheriji, Y.; Wise, A.; Fulzele, S.; Mehra, P.; Goldring, M.B.; Gerstenfeld, L.C.; Bais, M.V. Anabolic role of lysyl oxidase like-2 in cartilage of knee and temporomandibular joints with osteoarthritis. Arthritis Res. Ther. 2017, 19, 179. [Google Scholar] [CrossRef] [PubMed]
- Bais, M.V.; Goldring, M.B. LOXL2 as a protective in osteoarthritis cartilage. Aging (Albany NY) 2017, 9, 2024–2025. [Google Scholar] [CrossRef] [Green Version]
- Kaemmerer, W.F. How will the field of gene therapy survive its success? Bioeng. Transl. Med. 2018, 3, 166–177. [Google Scholar] [CrossRef]
- Evans, C.H.; Ghivizzani, S.C.; Robbins, P.D. Gene Delivery to Joints by Intra-Articular Injection. Hum. Gene Ther. 2018, 29, 2–14. [Google Scholar] [CrossRef]
- Chen, B.; Qin, J.; Wang, H.; Magdalou, J.; Chen, L. Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits. Exp. Mol. Med. 2010, 42, 684–695. [Google Scholar] [CrossRef]
- Lee, C.S.; Bishop, E.S.; Zhang, R.; Yu, X.; Farina, E.M.; Yan, S.; Zhao, C.; Zheng, Z.; Shu, Y.; Wu, X.; et al. Adenovirus-Mediated Gene Delivery: Potential Applications for Gene and Cell-Based Therapies in the New Era of Personalized Medicine. Genes Dis. 2017, 4, 43–63. [Google Scholar] [CrossRef] [PubMed]
- Li, Y.; Lacerda, D.A.; Warman, M.L.; Beier, D.R.; Yoshioka, H.; Ninomiya, Y.; Oxford, J.T.; Morris, N.P.; Andrikopoulos, K.; Ramirez, F.; et al. A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell 1995, 80, 423–430. [Google Scholar] [CrossRef] [Green Version]
- Duance, V.C.; Wotton, S.F. Changes in the distribution of mammalian cartilage collagens with age. Biochem. Soc. Trans. 1991, 19, 376S. [Google Scholar] [CrossRef] [PubMed]
- Salazar, A.; Polur, I.; Servais, J.M.; Li, Y.; Xu, L. Delayed progression of condylar cartilage degeneration, by reduction of the discoidin domain receptor 2, in the temporomandibular joints of osteoarthritic mouse models. J. Oral. Pathol. Med. 2014, 43, 317–321. [Google Scholar] [CrossRef] [PubMed]
- Xu, L.; Flahiff, C.M.; Waldman, B.A.; Wu, D.; Olsen, B.R.; Setton, L.A.; Li, Y. Osteoarthritis-like changes and decreased mechanical function of articular cartilage in the joints of mice with the chondrodysplasia gene (cho). Arthritis Rheum. 2003, 48, 2509–2518. [Google Scholar] [CrossRef] [PubMed]
- Elsaid, K.A.; Ubhe, A.; Shaman, Z.; D’Souza, G. Intra-articular interleukin-1 receptor antagonist (IL1-ra) microspheres for posttraumatic osteoarthritis: In vitro biological activity and in vivo disease modifying effect. J. Exp. Orthop. 2016, 3, 18. [Google Scholar] [CrossRef] [PubMed]
- Jotanovic, Z.; Mihelic, R.; Sestan, B.; Dembic, Z. Role of interleukin-1 inhibitors in osteoarthritis: An evidence-based review. Drugs Aging 2012, 29, 343–358. [Google Scholar] [CrossRef]
- Martin, A.; Salvador, F.; Moreno-Bueno, G.; Floristan, A.; Ruiz-Herguido, C.; Cuevas, E.P.; Morales, S.; Santos, V.; Csiszar, K.; Dubus, P.; et al. Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression. EMBO J. 2015, 34, 1090–1109. [Google Scholar] [CrossRef]
- Stevenson, G.W.; Mercer, H.; Cormier, J.; Dunbar, C.; Benoit, L.; Adams, C.; Jezierski, J.; Luginbuhl, A.; Bilsky, E.J. Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: Implications for preclinical behavioral assessment of chronic pain. Pharm. Biochem. Behav. 2011, 98, 35–42. [Google Scholar] [CrossRef] [Green Version]
- Cobos, E.J.; Ghasemlou, N.; Araldi, D.; Segal, D.; Duong, K.; Woolf, C.J. Inflammation-induced decrease in voluntary wheel running in mice: A nonreflexive test for evaluating inflammatory pain and analgesia. Pain 2012, 153, 876–884. [Google Scholar] [CrossRef]
- Xu, L.; Servais, J.; Polur, I.; Kim, D.; Lee, P.L.; Chung, K.; Li, Y. Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in mice. Arthritis Rheum. 2010, 62, 2736–2744. [Google Scholar] [CrossRef] [Green Version]
- Xu, L.; Peng, H.; Wu, D.; Hu, K.; Goldring, M.B.; Olsen, B.R.; Li, Y. Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J. Biol. Chem. 2005, 280, 548–555. [Google Scholar] [CrossRef]
- Wang, M.; Sampson, E.R.; Jin, H.; Li, J.; Ke, Q.H.; Im, H.J.; Chen, D. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res. Ther. 2013, 15, R5. [Google Scholar] [CrossRef]
- Makris, E.A.; Responte, D.J.; Paschos, N.K.; Hu, J.C.; Athanasiou, K.A. Developing functional musculoskeletal tissues through hypoxia and lysyl oxidase-induced collagen cross-linking. Proc. Natl. Acad. Sci. USA 2014, 111, E4832–E4841. [Google Scholar] [CrossRef]
- Olivotto, E.; Otero, M.; Astolfi, A.; Platano, D.; Facchini, A.; Pagani, S.; Flamigni, F.; Facchini, A.; Goldring, M.B.; Borzi, R.M.; et al. IKKalpha/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation. PLoS ONE 2013, 8, e73024. [Google Scholar] [CrossRef]
- Ala-Kokko, L.; Baldwin, C.T.; Moskowitz, R.W.; Prockop, D.J. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc. Natl. Acad. Sci. USA 1990, 87, 6565–6568. [Google Scholar] [CrossRef]
- Vos, L.M.; Kuijer, R.; Huddleston Slater, J.J.; Stegenga, B. Alteration of cartilage degeneration and inflammation markers in temporomandibular joint osteoarthritis occurs proportionally. J. Oral Maxillofac. Surg. 2013, 71, 1659–1664. [Google Scholar] [CrossRef]
- Moreno-Bueno, G.; Salvador, F.; Martin, A.; Floristan, A.; Cuevas, E.P.; Santos, V.; Montes, A.; Morales, S.; Castilla, M.A.; Rojo-Sebastian, A.; et al. Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas. EMBO Mol. Med. 2011, 3, 528–544. [Google Scholar] [CrossRef]
- Cuevas, E.P.; Moreno-Bueno, G.; Canesin, G.; Santos, V.; Portillo, F.; Cano, A. LOXL2 catalytically inactive mutants mediate epithelial-to-mesenchymal transition. Biol. Open 2014, 3, 129–137. [Google Scholar] [CrossRef]
- Salvador, F.; Martin, A.; Lopez-Menendez, C.; Moreno-Bueno, G.; Santos, V.; Vazquez-Naharro, A.; Santamaria, P.G.; Morales, S.; Dubus, P.R.; Muinelo-Romay, L.; et al. Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer. Cancer Res. 2017, 77, 5846–5859. [Google Scholar] [CrossRef]
- Bais, M.V.; Wigner, N.; Young, M.; Toholka, R.; Graves, D.T.; Morgan, E.F.; Gerstenfeld, L.C.; Einhorn, T.A. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells. Bone 2009, 45, 254–266. [Google Scholar] [CrossRef] [Green Version]
- Fentz, J.; Kjobsted, R.; Birk, J.B.; Jordy, A.B.; Jeppesen, J.; Thorsen, K.; Schjerling, P.; Kiens, B.; Jessen, N.; Viollet, B.; et al. AMPKα is critical for enhancing skeletal muscle fatty acid utilization during in vivo exercise in mice. FASEB J. 2015, 29, 1725–1738. [Google Scholar] [CrossRef]
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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.; et al. Lysyl Oxidase-Like 2 Protects against Progressive and Aging Related Knee Joint Osteoarthritis in Mice. Int. J. Mol. Sci. 2019, 20, 4798. https://doi.org/10.3390/ijms20194798
Tashkandi M, Ali F, Alsaqer S, Alhousami T, Cano A, Martin A, Salvador F, Portillo F, C. Gerstenfeld L, Goldring MB, et al. Lysyl Oxidase-Like 2 Protects against Progressive and Aging Related Knee Joint Osteoarthritis in Mice. International Journal of Molecular Sciences. 2019; 20(19):4798. https://doi.org/10.3390/ijms20194798
Chicago/Turabian StyleTashkandi, Mustafa, Faiza Ali, Saqer Alsaqer, Thabet Alhousami, Amparo Cano, Alberto Martin, Fernando Salvador, Francisco Portillo, Louis C. Gerstenfeld, Mary B. Goldring, and et al. 2019. "Lysyl Oxidase-Like 2 Protects against Progressive and Aging Related Knee Joint Osteoarthritis in Mice" International Journal of Molecular Sciences 20, no. 19: 4798. https://doi.org/10.3390/ijms20194798