title: Altered material properties are responsible for bone fragility in rats with chronic kidney injury.
abstract: Chronic kidney disease (CKD) is associated with an increased risk of fragility fractures, but the underlying pathophysiological mechanism remains obscure. We performed an in vivo experimental study to examine the roles of uremia and abnormal mineral/parathyroid metabolism in the development of bone metabolic abnormalities in uremic rats. Male Sprague-Dawley rats were divided into four groups, comprising sham operation (high turnover bone control=HTB-Cont), 5/6-nephrectomy (high turnover bone nephrectomized=HTB-Nx), thyroparathyroidectomy (low turnover bone control=LTB-Cont), and thyroparathyroidectomy plus 5/6 nephrectomy (low turnover bone nephrectomized=LTB-Nx), and maintained for 16 weeks. Uremia was successfully created in the LTB-Nx and HTB-Nx groups, while hyperparathyroidism was only found in the HTB-Nx group. Cancellous bone histomorphometry revealed significantly higher bone turnover in the HTB-Nx group than in the LTB-Nx group. Storage modulus at 1 Hz and tan delta in cortical bone of the femur, which represent the viscoelastic mechanical properties, were significantly lower in both Nx groups than in the Cont groups regardless of bone metabolism. Pentosidine-to-matrix ratio was increased and crystallinity was decreased in both Nx groups regardless of bone turnover. Mineral-to-matrix ratio was significantly decreased in the HTB-Nx group, but increased in the LTB-Nx group. Enzymatic collagen crosslinks were decreased in the HTB-Nx group. The degree of orientation of the c-axis in carbonated hydroxyapatite (biological apatite=BAp) crystallites was decreased in both Nx groups regardless of bone metabolism. Stepwise multivariate regression revealed that pentosodine-to-matrix ratio and BAp preferential c-axis orientation were significantly associated with storage modulus and tan delta. In conclusion, bone elastic mechanical properties deteriorated regardless of bone metabolism or bone mass in rats with chronic kidney injury. Various changes in bone mineral properties were associated with CKD, including abnormal parathyroid function, impaired bone turnover, and uremia associated with the accumulation of uremic toxins, were responsible for these changes. Pentosidine-to-matrix ratio and BAp orientation at position 5 were the two meaningful determinants of elastic bone mechanical strength, and both factors were associated with the severity of uremia, but not parathyroid function or bone metabolism. These two factors may account for the increased bone fragility among CKD patients.
authors.affiliation: Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Division of Blood Purification Therapy, Niigata University Medical and Dental Hospital, Niigata, Japan. Electronic address: jjkaz@med.niigata-u.ac.jp.
authors.forename: Junichiro J
authors.initials: JJ
authors.lastname: Kazama
authors.affiliation: Responsible Care Planning Division, Kureha Corporation, Iwaki, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamato
authors.affiliation: Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, Osaka, Japan.
authors.forename: Aira
authors.initials: A
authors.lastname: Matsugaki
authors.affiliation: Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, Osaka, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Division of Nephrology and Metabolism, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000502:physiology; D015519:Bone Density / Q000502:physiology; D001847:Bone Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism*; D016723:Bone Remodeling / Q000502:physiology; D005269:Femur / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008297:Male; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000000981:diagnostic imaging* / Q000378:metabolism*; D014961:X-Ray Diffraction
keywords: Biological apatite; Chronic kidney injury; Elastic bone mechanical property; Pentosidine