title: Cyclophilin D Knock-Out Mice Show Enhanced Resistance to Osteoporosis and to Metabolic Changes Observed in Aging Bone.
abstract: Pathogenic factors associated with aging, such as oxidative stress and hormone depletion converge on mitochondria and impair their function via opening of the mitochondrial permeability transition pore (MPTP). The MPTP is a large non-selective pore regulated by cyclophilin D (CypD) that disrupts mitochondrial membrane integrity. MPTP involvement has been firmly established in degenerative processes in heart, brain, and muscle. Bone has high energy demands and is therefore expected to be highly sensitive to mitochondrial dysfunction. Despite this, the role of mitochondria and the MPTP in bone maintenance and bone pathology has not been elucidated. Our goal was to determine whether mitochondria are impaired in aging bone and to see if protecting mitochondria from MPTP opening via CypD deletion protects against bone loss. We found that bone mass, strength, and formation progressively decline over the course of 18 months in C57BL/6J mice. Using metabolomics and electron microscopy, we determined that oxidative metabolism is impaired in aging bone leading to a glycolytic shift, imbalance in nucleotides, and decreased NAD+/NADH ratio. Mitochondria in osteocytes appear swollen which is a major marker of MPTP opening. CypD deletion by CypD knockout mouse model (CypD KO) protects against bone loss in 13- and 18-month-old mice and prevents decline in bone formation and mitochondrial changes observed in wild type C57BL/6J mice. Together, these data demonstrate that mitochondria are impaired in aging bone and that CypD deletion protects against this impairment to prevent bone loss. This implicates CypD-regulated MPTP and mitochondrial dysfunction in the impairment of bone cells and in aging-related bone loss. Our findings suggest mitochondrial metabolism as a new target for bone therapeutics and inhibition of CypD as a novel strategy against bone loss.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Laura C
authors.identifier: 0000-0002-0167-4133
authors.initials: LC
authors.lastname: Shum
authors.affiliation: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: White
authors.affiliation: Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.affiliation: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.|Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Karen L de Mesy
authors.initials: KL
authors.lastname: Bentley
authors.affiliation: Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.affiliation: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.|Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Jonason
authors.affiliation: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.|Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Eliseev
mesh_terms: D000367:Age Factors; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency*; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D055114:X-Ray Microtomography
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D021983:Cyclophilins