title: Protective effects of mitochondria-targeted antioxidants and statins on cholesterol-induced osteoarthritis.
abstract: The contribution of metabolic factors on the severity of osteoarthritis (OA) is not fully appreciated. This study aimed to define the effects of hypercholesterolemia on the progression of OA. Apolipoprotein E-deficient (ApoE-/-) mice and rats with diet-induced hypercholesterolemia (DIHC) rats were used to explore the effects of hypercholesterolemia on the progression of OA. Both models exhibited OA-like changes, characterized primarily by a loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and cartilage degradation. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high-cholesterol diet compared with controls. Clinically relevant doses of free cholesterol resulted in mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), and increased expression of degenerative and hypertrophic markers in chondrocytes and breakdown of the cartilage matrix. We showed that the severity of diet-induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that hypercholesterolemia precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.-Farnaghi, S., Prasadam, I., Cai, G., Friis, T., Du, Z., Crawford, R., Mao, X., Xiao, Y. Protective effects of mitochondria-targeted antioxidants and statins on cholesterol-induced osteoarthritis.
authors.affiliation: Institute of Health and Biomedical Innovation, School of Chemistry, Physics, and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Saba
authors.initials: S
authors.lastname: Farnaghi
authors.affiliation: Institute of Health and Biomedical Innovation, School of Chemistry, Physics, and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Indira
authors.initials: I
authors.lastname: Prasadam
authors.affiliation: Department of Orthopaedic Surgery, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Guangping
authors.initials: G
authors.lastname: Cai
authors.affiliation: Institute of Health and Biomedical Innovation, School of Chemistry, Physics, and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Thor
authors.initials: T
authors.lastname: Friis
authors.affiliation: Institute of Health and Biomedical Innovation, School of Chemistry, Physics, and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Du
authors.affiliation: Institute of Health and Biomedical Innovation, School of Chemistry, Physics, and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.|Department of Orthopedics, Prince Charles Hospital, Brisbane, Queensland, Australia; and.
authors.forename: Ross
authors.initials: R
authors.lastname: Crawford
authors.affiliation: Department of Orthopaedic Surgery, Second Xiangya Hospital, Central South University, Changsha, China maoxinzhan72@126.com.
authors.forename: Xinzhan
authors.initials: X
authors.lastname: Mao
authors.affiliation: Institute of Health and Biomedical Innovation, School of Chemistry, Physics, and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland, Australia; yin.xiao@qut.edu.au.|Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000975:Antioxidants; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D000069059:Atorvastatin / Q000494:pharmacology*; D016723:Bone Remodeling; D002784:Cholesterol / Q000097:blood / Q000633:toxicity*; D019902:Chondrocytes / Q000187:drug effects; D004041:Dietary Fats; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced* / Q000150:complications; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects*; D010003:Osteoarthritis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000924:Anticholesteremic Agents; D000975:Antioxidants; D001057:Apolipoproteins E; D004041:Dietary Fats; D002784:Cholesterol; D000069059:Atorvastatin
keywords: ApoE−/− mice; cartilage; hypercholesterolemia; oxidative stress