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Krishnan S, Aston CE, Chadwick J, Gulati S, Wang H, Sisson SB, Misra M, Chernausek SD. Collagen glycosylation, hip structural analysis, and trabecular bone score in adolescents with type 1 diabetes: a cross-sectional study. Diabetol Metab Syndr 2025; 17:113. [PMID: 40176172 PMCID: PMC11963267 DOI: 10.1186/s13098-025-01677-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 03/19/2025] [Indexed: 04/04/2025] Open
Abstract
Both type 1 and type 2 diabetes mellitus (T1D and T2D) are associated with poor bone health and an increased risk of fracture in adults. However, there are limited data regarding the effects of diabetes on the growing skeleton, particularly during adolescence, the time of peak bone mineral accretion. The purpose of this study was to examine differences in markers of bone health and factors that influence bone health in White adolescents and young adults with well-controlled T1D (n = 17; Average A1C 7.45 ± 1.15%) and control participants without T1D (n = 13). Age across both groups was similar (17.41 ± 1.62 years for T1D vs. 17.46 ± 1.45 years for controls) as was BMI and height. Bone density was measured at the lumbar spine, whole body, and proximal femur sites using the GE HealthCare's Lunar iDXA (GE; v11-30.062) in all subjects. Hip structural analysis (HSA) was performed at the proximal femur and Trabecular Bone Score (TBS) was calculated from AP spine image using Trabecular Osteo Software from Medimaps. Markers of bone formation, resorption, serum sclerostin and urine pentosidine were measured in all subjects. No difference in total body bone mineral density (BMD), lumbar spine BMD, lumbar spine BMAD, dual femur BMD, HSA variables or TBS measures were noted between subjects with T1D and controls. However, duration of diabetes had a significant negative correlation (p: 0.035) with cross-sectional moment of inertia (a measure of resistance to bending forces) in subjects with T1D. IGF-1 levels were marginally lower in the group with T1D (p:0.06) and had a significant inverse relationship (r: -0.406, p:0.026) with mean hip axis angle; a known predictor of hip fractures. TBS score had a marginally significant negative correlation with urinary pentosidine (a marker for collagen glycosylation) across both groups after adjusting for age (r: -0.343, p: 0.07), suggesting increased collagen glycosylation has an adverse impact on bone microarchitecture. CLINICAL TRIAL NUMBER: Not applicable.
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Affiliation(s)
- Sowmya Krishnan
- Department of Pediatrics, Harold Hamm Diabetes Center, University of Oklahoma Health Science Center, Oklahoma City, USA.
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA.
| | - Christopher E Aston
- Department of Pediatrics, Biomedical and Behavioral Methodology Core, University of Oklahoma Health Science Center, Oklahoma City, USA
| | - Jennifer Chadwick
- Department of Pediatrics, Harold Hamm Diabetes Center, University of Oklahoma Health Science Center, Oklahoma City, USA
| | - Shelly Gulati
- Department of Pediatrics, Harold Hamm Diabetes Center, University of Oklahoma Health Science Center, Oklahoma City, USA
| | - Huaiwen Wang
- University of Oklahoma Health Science Center, Institutional Research Core Facility, Oklahoma City, OK, 73104, USA
| | - Susan B Sisson
- Department of Nutrition Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Madhusmita Misra
- Division of Pediatric Endocrinology, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA
| | - Steven D Chernausek
- Department of Pediatrics, Harold Hamm Diabetes Center, University of Oklahoma Health Science Center, Oklahoma City, USA
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Baumann S, Sewing L, Traechslin C, Verhagen-Kamerbeek W, Grize L, Kraenzlin M, Meier C. Serum Pentosidine in Relation to Obesity in Patients with Type 2 Diabetes and Healthy Controls. Calcif Tissue Int 2025; 116:25. [PMID: 39777548 PMCID: PMC11706925 DOI: 10.1007/s00223-024-01338-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025]
Abstract
Pentosidine (PEN), a surrogate marker of advanced glycation end-product formation, reflects increased non-enzymatic cross-linking in bone collagen, which is thought to be an important determinant of bone fragility in type 2 diabetes mellitus (T2DM). We aimed to investigate serum concentrations of PEN in patients with T2DM and controls without T2DM and to examine its relationship with bone parameters and metabolic state such as glycaemic control, insulin resistance and body weight. In a cross-sectional study-design, data from postmenopausal women and men with T2DM (n = 110) and controls without T2DM (n = 111) were evaluated. Serum PEN was measured using an ELISA-based assay (CSB-E09415h, Cusabio). In addition, biochemical markers of glucose metabolism and bone turnover markers were measured. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry. After adjustment for age, gender and body mass index (BMI), serum PEN was significantly higher in patients with T2DM compared to controls (p = 0.02) and most prominently in women with T2DM (p = 0.09). We found a strong association of serum PEN concentrations with BMI in the entire study population (R = 0.43, p < 0.001) as well as in patients with T2DM (R = 0.28, p < 0.01). While bone turnover markers were significantly decreased, and BMD increased in patients with T2DM, only weak or no associations were observed between these skeletal surrogate markers and serum PEN. We conclude that serum PEN is strongly associated with BMI with highest levels in obese women with T2DM. Adjustment for patient's weight is needed when evaluating serum PEN levels in patients with T2DM.Clinical Trial Information: NCT02551315.
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Affiliation(s)
- Sandra Baumann
- Division of Endocrinology and Diabetes, Spital Emmental, Burgdorf, Switzerland
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Lilian Sewing
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Cyril Traechslin
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Wilma Verhagen-Kamerbeek
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Leticia Grize
- Swiss Tropical and Public Health Institute and University of Basel, Basel, Switzerland
| | | | - Christian Meier
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland.
- Endocrine Clinic and Laboratory, Basel, Switzerland.
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Matsuno K, Ueda K, Saito M, Kamii M, Tsuda A, Kawabata A, Morikawa A, Okamoto A. Pilot study of the effect of surgical menopause on bone mineral density and quality in patients with gynecological malignancies. J Obstet Gynaecol Res 2025; 51:e16141. [PMID: 39530312 PMCID: PMC11635186 DOI: 10.1111/jog.16141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
AIM To investigate the effects of surgical menopause on bone mineral density and bone quality because bilateral salpingo-oophorectomy for the treatment of gynecological malignancies is common even in premenopausal patients. This study is prospective one of bone mineral density and quality measurements after surgery for perimenopausal gynecologic malignancies. METHODS In 50 women who underwent surgical menopause for a diagnosis of gynecological malignancies, bone mineral density (BMD), blood levels of tartrate-resistant acid phosphatase 5b (TRACP-5b) and bone-specific alkaline phosphatase (BAP) as bone metabolism markers, and urinary pentosidine level as bone quality marker were measured before surgery and at multiple points up to 24 months after surgery. RESULTS In a group of 22 patients who did not undergo hormone replacement therapy (HRT) (HRT- group), BMD of the lumbar spine and total hip continued to decrease significantly from 6 months postoperatively. Percentages of changes in BMD progressively increased over time after surgery. TRACP-5b and urinary pentosidine levels significantly increased 6 months postoperatively compared with preoperative levels. Comparisons between 10 patients who underwent HRT (HRT+ group) and the HRT- group revealed significant reductions in the percentage of change in lumbar spine BMD only and TRACP-5b and urinary pentosidine levels 12 months postoperatively in the former group. CONCLUSIONS In this pilot study, we showed that BMD and bone-related markers are altered in patients with surgical menopause. It also suggested that HRT may reduce these influences on bone metabolism.
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Affiliation(s)
- Kanae Matsuno
- Department of Gynecology and ObstetricsThe Jikei University School of MedicineMinato‐kuTokyoJapan
| | - Kazu Ueda
- Department of GynecologyInternational University of Health and Welfare, Mita HospitalMinato‐kuTokyoJapan
| | - Mitsuru Saito
- Department of Orthopedic SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Misato Kamii
- Department of Gynecology and ObstetricsThe Jikei University School of MedicineMinato‐kuTokyoJapan
| | - Akina Tsuda
- Department of Gynecology and ObstetricsThe Jikei University School of MedicineMinato‐kuTokyoJapan
| | - Ayako Kawabata
- Department of Gynecology and ObstetricsThe Jikei University School of MedicineMinato‐kuTokyoJapan
| | - Asuka Morikawa
- Department of Gynecology and ObstetricsThe Jikei University School of MedicineMinato‐kuTokyoJapan
| | - Aikou Okamoto
- Department of Gynecology and ObstetricsThe Jikei University School of MedicineMinato‐kuTokyoJapan
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Voziyan P, Brown KL, Uppuganti S, Leser M, Rose KL, Nyman JS. A map of glycation and glycoxidation sites in collagen I of human cortical bone: Effects of sex and type 2 diabetes. Bone 2024; 187:117209. [PMID: 39047900 PMCID: PMC11875209 DOI: 10.1016/j.bone.2024.117209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/19/2024] [Accepted: 07/21/2024] [Indexed: 07/27/2024]
Abstract
Complications of diabetes is a major health problem affecting multiple organs including bone, where the chronic disease increases the risk of fragility fractures. One hypothesis suggests a pathogenic role for hyperglycemia-induced modification of proteins, a.k.a. advanced glycation end products (AGEs), resulting in structural and functional damage to bone extracellular matrix (ECM). Evidence supporting this hypothesis has been limited by the lack of comprehensive information about the location of AGEs that accumulate in vivo at specific sites within the proteins of bone ECM. Analyzing extracts from cortical bone of cadaveric femurs by liquid chromatography tandem mass spectrometry, we generated a quantitative AGE map of human collagen I for male and female adult donors with and without diabetes. The map describes the chemical nature, sequence position, and levels of four major physiological AGEs, e.g. carboxymethyllysine, and an AGE precursor fructosyllysine within the collagen I triple-helical region. The important features of the map are: 1) high map reproducibility in the individual bone extracts, i.e. 20 male and 20 female donors; 2) localization of modifications to distinct clusters: 10 clusters containing 34 AGE sites in male donors and 9 clusters containing 28 sites in female donors; 3) significant increases in modification levels in diabetes at multiple sites: 26 out of 34 sites in males and in 17 out of 28 sites in females; and 4) generally higher modification levels in male vs. female donors. Moreover, the AGE levels at multiple individual sites correlated with total bone pentosidine levels in male but not in female donors. Molecular dynamics simulations and molecular modeling predicted significant impact of modifications on solvent exposure, charge distribution, and hydrophobicity of the triple helix as well as disruptions to the structure of collagen I fibril. In summary, the AGE map of collagen I revealed diabetes-induced, sex-specific non-enzymatic modifications at distinct triple helical sites that can disrupt collagen structure, thus proposing a specific mechanism of AGE contribution to diabetic complications in human bone.
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Affiliation(s)
- Paul Voziyan
- Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
| | - Kyle L Brown
- Vanderbilt Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA
| | - Sasidhar Uppuganti
- Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Micheal Leser
- Department of Biochemistry and Proteomics Core, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232, USA
| | - Kristie Lindsey Rose
- Department of Biochemistry and Proteomics Core, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232, USA
| | - Jeffry S Nyman
- Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
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Takata T, Inoue S, Kunii K, Masauji T, Miyazawa K. Slot Blot- and Electrospray Ionization-Mass Spectrometry/Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry-Based Novel Analysis Methods for the Identification and Quantification of Advanced Glycation End-Products in the Urine. Int J Mol Sci 2024; 25:9632. [PMID: 39273579 PMCID: PMC11395049 DOI: 10.3390/ijms25179632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/02/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Proteins, saccharides, and low molecular organic compounds in the blood, urine, and saliva could potentially serve as biomarkers for diseases related to diet, lifestyle, and the use of illegal drugs. Lifestyle-related diseases (LSRDs) such as diabetes mellitus (DM), non-alcoholic steatohepatitis, cardiovascular disease, hypertension, kidney disease, and osteoporosis could develop into life-threatening conditions. Therefore, there is an urgent need to develop biomarkers for their early diagnosis. Advanced glycation end-products (AGEs) are associated with LSRDs and may induce/promote LSRDs. The presence of AGEs in body fluids could represent a biomarker of LSRDs. Urine samples could potentially be used for detecting AGEs, as urine collection is convenient and non-invasive. However, the detection and identification of AGE-modified proteins in the urine could be challenging, as their concentrations in the urine might be extremely low. To address this issue, we propose a new analytical approach. This strategy employs a method previously introduced by us, which combines slot blotting, our unique lysis buffer named Takata's lysis buffer, and a polyvinylidene difluoride membrane, in conjunction with electrospray ionization-mass spectrometry (ESI)/matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). This novel strategy could be used to detect AGE-modified proteins, AGE-modified peptides, and free-type AGEs in urine samples.
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Affiliation(s)
- Takanobu Takata
- Division of Molecular and Genetic Biology, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
- Department of Pharmacy, Kanazawa Medical University Hospital, Uchinada 920-0293, Ishikawa, Japan
| | - Shinya Inoue
- Department of Urology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
- Inoue Iin Clinic, Kusatsu 525-0034, Shiga, Japan
| | - Kenshiro Kunii
- Department of Urology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
| | - Togen Masauji
- Department of Pharmacy, Kanazawa Medical University Hospital, Uchinada 920-0293, Ishikawa, Japan
| | - Katsuhito Miyazawa
- Department of Urology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
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Elnunu IS, Redmond JN, Obata Y, Woolley W, Kammer DS, Acevedo C. Increased AGE Cross-Linking Reduces the Mechanical Properties of Osteons. JOM (WARRENDALE, PA. : 1989) 2024; 76:5692-5702. [PMID: 39318440 PMCID: PMC11417058 DOI: 10.1007/s11837-024-06716-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 06/10/2024] [Indexed: 09/26/2024]
Abstract
The osteon is the primary structural component of bone, contributing significantly to its unique toughness and strength. Despite extensive research on osteonal structure, the properties of osteons have not been fully investigated, particularly within the context of bone fragility diseases like type 2 diabetes mellitus (T2DM). This study aims to isolate osteons from bovine bone, simulate the effects of increased advanced glycation end-products (AGEs) in T2DM through ribosylation, and evaluate the mechanical properties of isolated osteons. Osteons extracted from the posterior section of bovine femur mid-diaphysis were processed to achieve a sub-millimeter scale for microscale imaging. Subsequently, synchrotron radiation micro-computed tomography was employed to precisely localize and isolate the osteon internally. While comparable elastic properties were observed between control and ribosylated osteons, the presence of AGEs led to decreased strain to failure. Young's modulus was quantified (9.9 ± 4.9 GPa and 8.7 ± 3 GPa, respectively), aligning closely with existing literature. This study presents a novel method for the extraction and isolation of osteons from bone and shows the detrimental effect of AGEs at the osteonal level. Supplementary Information The online version contains supplementary material available at 10.1007/s11837-024-06716-x.
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Affiliation(s)
- Ihsan S Elnunu
- Department of Mechanical Engineering, University of Utah, Salt Lake City, UT 84112 USA
| | - Jessica N Redmond
- Department of Mechanical Engineering, University of Utah, Salt Lake City, UT 84112 USA
| | - Yoshihiro Obata
- Department of Mechanical Engineering, University of Utah, Salt Lake City, UT 84112 USA
- Department of Mechanical and Aerospace Engineering, University of California San Diego, Engineers Ln, San Diego, CA 92161 USA
| | - William Woolley
- Department of Mechanical Engineering, University of Utah, Salt Lake City, UT 84112 USA
- Department of Mechanical and Aerospace Engineering, University of California San Diego, Engineers Ln, San Diego, CA 92161 USA
| | - David S Kammer
- Institute for Building Materials, ETH Zurich, Laura-Hezner-Weg 7, 8093 Zurich, Switzerland
| | - Claire Acevedo
- Department of Mechanical Engineering, University of Utah, Salt Lake City, UT 84112 USA
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112 USA
- Department of Mechanical and Aerospace Engineering, University of California San Diego, Engineers Ln, San Diego, CA 92161 USA
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Urano T, Kuroda T, Uenishi K, Shiraki M. Serum branched-chain amino acid levels are associated with fracture risk in Japanese women. Geriatr Gerontol Int 2024; 24:603-608. [PMID: 38745353 DOI: 10.1111/ggi.14896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/24/2024] [Accepted: 05/04/2024] [Indexed: 05/16/2024]
Abstract
AIM Branched-chain amino acids (BCAAs) have been shown to exert beneficial effects on muscle and bone metabolism; however, no studies to date have investigated whether BCAAs have beneficial effects on bone fractures. Herein, we aim to prospectively investigate the relationship between serum BCAA concentrations and the occurrence of vertebral fractures (VFs) in Japanese women. METHODS During the observation period (7.5 ± 6.1 years), 188 of 983 participants experienced VF. Kaplan-Meier analyses were conducted to examine time-dependent variations in the vertebral compression fracture occurrence rate. Patients were stratified into quartiles based on serum BCAA concentration for this analysis. RESULTS The analysis results indicated that the group with the lowest BCAA level developed VFs significantly earlier and with a higher frequency than the other groups (P < 0.001). A Cox proportional hazards model showed that BCAA concentration was a significant risk factor for incident fracture, even after adjusting for possible confounding factors. A series of multiple regression analyses were performed to identify factors related to serum BCAA concentration, with the results identifying levels of glycated hemoglobin (P < 0.001), adiponectin (P < 0.001), and NOx (P = 0.011) as significant factors associated with serum BCAA. CONCLUSIONS Overall, the present study revealed that a lower serum BCAA level was an independent risk factor for incident VF in postmenopausal women. Geriatr Gerontol Int 2024; 24: 603-608.
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Affiliation(s)
- Tomohiko Urano
- Department of Geriatric Medicine, International University of Health and Welfare School of Medicine, Narita City, Japan
| | | | - Kazuhiro Uenishi
- Division of Nutritional Physiology, Kagawa Nutrition University, Sakado, Japan
| | - Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, Azumino City, Japan
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Urano T, Kuroda T, Shiraki M. Nutritional and inflammation factors associated with current frailty level and effect of co-morbidities on the progression of frailty. Geriatr Gerontol Int 2024; 24:523-528. [PMID: 38618879 DOI: 10.1111/ggi.14873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/16/2024]
Abstract
AIM Frailty is defined as extreme vulnerability, a syndrome that exposes the individual to a higher risk of disability. While risk factors for frailty have been gradually uncovered, the full identification of biochemical factors and co-morbidities influencing frailty remains incomplete. METHODS Cross-sectional and longitudinal analyses were performed to elucidate the risk factors for the prevalence and progression of frailty. The study included 1035 Japanese female outpatients. At baseline, biochemical markers were measured. Co-morbidities included diabetes mellitus, dyslipidemia, hypertension, vertebral osteoarthritis, and osteoporosis. Frailty levels were assessed using frailty scores ranging from 0 to 5. Prevalence of frailty was judged by a score of 3 or above, and progression was judged by an increase in the frailty score during the observation period. Multiple regression analysis was used for the cross-sectional analysis, and the Cox hazard model was used for the longitudinal analysis. RESULTS Of the 1035 selected participants, 212 were diagnosed with frailty. Advanced age and log IL-6 and branched-chain amino acids (BCAA) levels were significant independent risk factors for frailty. Subjects were followed for 7.7 ± 5.9 years and progression was observed in 130 subjects. Older age, the absence of hyperlipidemia, the presence of osteoporosis, and lower frailty scores were identified as significant risk factors for frailty progression. CONCLUSIONS Inflammatory and nutritional markers exhibited significant associations with the current frailty status, whereas co-morbidities such as osteoporosis or hyperlipidemia emerged as independent risk or protective factors of future frailty progression. Geriatr Gerontol Int 2024; 24: 523-528.
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Affiliation(s)
- Tomohiko Urano
- Department of Geriatric Medicine, International University of Health and Welfare School of Medicine, Chiba, Japan
| | | | - Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, Nagano, Japan
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Kuroda T, Shiraki M, Saito M, Urano T. Spinal osteoarthritis is a risk of vertebral fractures in postmenopausal women. Sci Rep 2024; 14:3528. [PMID: 38347047 PMCID: PMC10861596 DOI: 10.1038/s41598-024-53994-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 02/07/2024] [Indexed: 02/15/2024] Open
Abstract
Recent studies have revealed that despite high bone mineral density (BMD), osteoarthritis (OA) is a risk factor for osteoporotic fractures. However, the relationship between spinal OA and vertebral fractures has not yet been fully investigated. This longitudinal analysis used a subset of ongoing cohort study consist with Japanese postmenopausal women. The prevalence of spinal OA was determined using Kellgren-Lawrence grading method. The incidence of vertebral fractures were determined by semiquantitative analysis of spinal X-ray films. The relationship between the presence of spinal OA and incidence of vertebral fractures was evaluated using the Cox regression analysis. In total, 1480 women were followed up for 8.1 ± 6.4 years. Among them, 923 were diagnosed with spinal OA, and incident vertebral fractures were observed in 473 participants. After adjusting for confounding variables, the spinal OA (≥ grade 2) was a significant predictor of incident vertebral fractures (hazard ratio, 1.52; 95% confidence interval: 1.19-1.93, p = 0.001). Using ROC analysis, the thresholds of lumbar BMD for incident vertebral fractures were 0.952 g/cm2 for patients with spinal OA and 0.753 g/cm2 for patients without spinal OA. The presence of spinal OA is a risk factor for incident vertebral fractures despite high lumbar BMD.
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Affiliation(s)
| | - Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, Azumino City, Nagano, Japan
| | - Mitsuru Saito
- Department of Orthopedic Surgery, Tokyo Jikei University, School of Medicine, Minato-ku, Tokyo, Japan
| | - Tomohiko Urano
- Department of Geriatric Medicine, International University of Health and Welfare School of Medicine, 4-3, Kozunomori, Narita City, Chiba, 286-8686, Japan.
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10
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Wang B, Vashishth D. Advanced glycation and glycoxidation end products in bone. Bone 2023; 176:116880. [PMID: 37579812 PMCID: PMC10529863 DOI: 10.1016/j.bone.2023.116880] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/21/2023] [Accepted: 08/11/2023] [Indexed: 08/16/2023]
Abstract
Hyperglycemia and oxidative stress, enhanced in diabetes and aging, result in excessive accumulation of advanced glycation and glycoxidation end products (AGEs/AGOEs) in bone. AGEs/AGOES are considered to be "the missing link" in explaining increased skeletal fragility with diabetes, aging, and osteoporosis where increased fracture risk cannot be solely explained by bone mass and/or fall incidences. AGEs/AGOEs disrupt bone turnover and deteriorate bone quality through alterations of organic matrix (collagen and non-collagenous proteins), mineral, and water content. AGEs and AGOEs are also associated with bone fragility in other conditions such as Alzheimer's disease, circadian rhythm disruption, and cancer. This review explains how AGEs and AGOEs accumulate in bone and impact bone quality and bone fracture, and how AGES/AGOEs are being targeted in preclinical and clinical investigations for inhibition or removal, and for prediction and management of diabetic, osteoporotic and insufficiency fractures.
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Affiliation(s)
- Bowen Wang
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Deepak Vashishth
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Rensselaer - Icahn School of Medicine at Mount Sinai Center for Engineering and Precision Medicine, New York, NY 10019, USA.
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11
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Ferreyro-Bravo F, Ceballos-Cruz Á, Urruchua-Rodríguez MJ, Martínez-Reyes G, Cortés-Pastrana C, Pacheco-Pantoja EL. Differential Association of Glycation Products with Bone Mineral Density and Fat Mass in Healthy and Diabetes Type 2 Subjects from Mexican Southeastern: A Cross Sectional Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1451. [PMID: 37629742 PMCID: PMC10456706 DOI: 10.3390/medicina59081451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 07/29/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023]
Abstract
Background: Glycation products have been linked to decreased bone mineral density (BMD) in a number of clinical settings. This study examined the correlation between early glycation products (HbA1c and glycated albumin (ALB-g)) and advanced glycation end products (pentosidine (PTD)) with BMD in two groups of participants: those with type 2 diabetes mellitus (DM2) and those without diabetes or any other comorbidities (noDM). All of the participants had resided in southeastern Mexico for a minimum of 10 years. Material and Methods: This study included 204 participants: 112 (55%) with DM2 and 92 (45%) healthy subjects. We utilized dual X-ray absorptiometry (DXA) to measure both the total and segment-specific BMD and adipose mass. In addition, the fasting blood glucose, HbA1c, PTD, and ALB-g parameters were measured. Correlation and logistic regression analyses were conducted. Results: There was an inverse correlation between PTD and BMD in all anatomical regions among postmenopausal women (PMW) in the DM2 group, whereas in non-PMW, only the waist-to-height ratio was statistically significant. A negative correlation was observed between HbA1c levels and BMD in the arms and legs of DM2 individuals. However, in the noDM group, a negative correlation was found between HbA1c levels and BMD in the pelvis, while a positive association was observed between HbA1c and indicators of adipose tissue. ALB-g, demonstrated a negative correlation with fat mass. After performing binary logistic regressions, the following odds ratios (OR) for osteopenia/osteoporosis risk were determined: PTD OR 1.1 (p = 0.047) for DM2 PMW, HbA1c OR 1.4 (p = 0.048), and fat mass content OR 1.011 (p = 0.023) for the entire sample. Conclusions: Glycation products are associated with BMD differentially depending on the analyzed anatomical segment, but PTD, HbA1c, and fat mass are significant predictors of low bone mass. In prospective studies, this association could be determined using other techniques involving three-dimensional analysis of bone architecture to evaluate bone architecture.
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Affiliation(s)
- Fernando Ferreyro-Bravo
- Health Sciences PhD Program, Universidad Católica de Murcia UCAM, 30107 Guadalupe de Maciascoque, Murcia, Spain;
| | - Ángel Ceballos-Cruz
- Health Sciences Division, School of Medicine, Anahuac Mayab University, Mérida 97308, Yuc., Mexico; (Á.C.-C.); (M.J.U.-R.); (G.M.-R.); (C.C.-P.)
| | - Mary Jose Urruchua-Rodríguez
- Health Sciences Division, School of Medicine, Anahuac Mayab University, Mérida 97308, Yuc., Mexico; (Á.C.-C.); (M.J.U.-R.); (G.M.-R.); (C.C.-P.)
| | - Gabriela Martínez-Reyes
- Health Sciences Division, School of Medicine, Anahuac Mayab University, Mérida 97308, Yuc., Mexico; (Á.C.-C.); (M.J.U.-R.); (G.M.-R.); (C.C.-P.)
| | - Carolina Cortés-Pastrana
- Health Sciences Division, School of Medicine, Anahuac Mayab University, Mérida 97308, Yuc., Mexico; (Á.C.-C.); (M.J.U.-R.); (G.M.-R.); (C.C.-P.)
| | - Elda Leonor Pacheco-Pantoja
- Health Sciences Division, School of Medicine, Anahuac Mayab University, Mérida 97308, Yuc., Mexico; (Á.C.-C.); (M.J.U.-R.); (G.M.-R.); (C.C.-P.)
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12
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Park JYC, King A, Björk V, English BW, Fedintsev A, Ewald CY. Strategic outline of interventions targeting extracellular matrix for promoting healthy longevity. Am J Physiol Cell Physiol 2023; 325:C90-C128. [PMID: 37154490 DOI: 10.1152/ajpcell.00060.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/10/2023]
Abstract
The extracellular matrix (ECM), composed of interlinked proteins outside of cells, is an important component of the human body that helps maintain tissue architecture and cellular homeostasis. As people age, the ECM undergoes changes that can lead to age-related morbidity and mortality. Despite its importance, ECM aging remains understudied in the field of geroscience. In this review, we discuss the core concepts of ECM integrity, outline the age-related challenges and subsequent pathologies and diseases, summarize diagnostic methods detecting a faulty ECM, and provide strategies targeting ECM homeostasis. To conceptualize this, we built a technology research tree to hierarchically visualize possible research sequences for studying ECM aging. This strategic framework will hopefully facilitate the development of future research on interventions to restore ECM integrity, which could potentially lead to the development of new drugs or therapeutic interventions promoting health during aging.
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Affiliation(s)
- Ji Young Cecilia Park
- Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
| | - Aaron King
- Foresight Institute, San Francisco, California, United States
| | | | - Bradley W English
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | | | - Collin Y Ewald
- Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
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13
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Cavati G, Pirrotta F, Merlotti D, Ceccarelli E, Calabrese M, Gennari L, Mingiano C. Role of Advanced Glycation End-Products and Oxidative Stress in Type-2-Diabetes-Induced Bone Fragility and Implications on Fracture Risk Stratification. Antioxidants (Basel) 2023; 12:antiox12040928. [PMID: 37107303 PMCID: PMC10135862 DOI: 10.3390/antiox12040928] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/06/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Type 2 diabetes (T2D) and osteoporosis (OP) are major causes of morbidity and mortality that have arelevant health and economic burden. Recent epidemiological evidence suggests that both of these disorders are often associated with each other and that T2D patients have an increased risk of fracture, making bone an additional target of diabetes. As occurs for other diabetic complications, the increased accumulation of advanced glycation end-products (AGEs) and oxidative stress represent the major mechanisms explaining bone fragility in T2D. Both of these conditions directly and indirectly (through the promotion of microvascular complications) impair the structural ductility of bone and negatively affect bone turnover, leading to impaired bone quality, rather than decreased bone density. This makes diabetes-induced bone fragility remarkably different from other forms of OP and represents a major challenge for fracture risk stratification, since either the measurement of BMD or the use of common diagnostic algorithms for OP have a poor predictive value. We review and discuss the role of AGEs and oxidative stress on the pathophysiology of bone fragility in T2D, providing some indications on how to improve fracture risk prediction in T2D patients.
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Affiliation(s)
- Guido Cavati
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Filippo Pirrotta
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Daniela Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Elena Ceccarelli
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Marco Calabrese
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Christian Mingiano
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
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14
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Kawashima I. Pregnancy and lactation-associated vertebral fragility fractures without low bone mineral density: A case report. J Orthop Sci 2023; 28:503-505. [PMID: 32891465 DOI: 10.1016/j.jos.2020.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Itaru Kawashima
- Department of Orthopaedic Surgery, Asahi University Hospital, 3-23 Hashimotocho, Gifu, Gifu 500-8523, Japan; Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan.
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15
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Mochizuki T, Yano K, Ikari K, Okazaki K. Comparison of different parameters between daily and twice-weekly teriparatide in postmenopausal women with severe osteoporosis. J Bone Miner Metab 2023; 41:220-226. [PMID: 36625920 DOI: 10.1007/s00774-022-01398-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Once-daily teriparatide (D-TPTD) and twice-weekly TPTD (W-TPTD), which are self-administered injections, are generally used in the treatment of severe osteoporosis. This study aimed to reveal the differences in the persistence, safety, and effectiveness of D-TPTD and W-TPTD. MATERIALS AND METHODS A total of 102 patients received D-TPTD (n = 51) and W-TPTD (n = 51). The bone mineral densities (BMD) of the lumbar spine, total hip, and femoral neck were measured using dual energy X-ray absorptiometry. The persistence and effectiveness of the two treatments were compared at 12 months. RESULTS The persistence in the D-TPTD and W-TPTD groups was 80.4% and 66.7% at 12 months, respectively (p = 0.178). The % changes (Δ) in BMD values from baseline for the lumbar spine in the D-TPTD were significantly higher than those in the W-TPTD (11.2% vs. 6.3%; p < 0.001) at 12 months. The ΔBMD values for the total hip (3.7% vs. 1.3%; p = 0.065) and femoral neck (2.2% vs. 1.6%; p = 0.489) did not differ significantly between the two groups at 12 months. The incidence of new morphological vertebral fractures in the D-TPTD and W-TPTD groups was 7.3% and 8.6%, respectively, at 12 months (p = 1.000). CONCLUSIONS Lumbar spine BMD (LS-BMD) was significantly increased. Moreover, ΔLS-BMD in the D-TPTD group was higher than that in the W-TPTD group. This study showed that the persistence, ΔTH-BMD, ΔFN-BMD and incidence of vertebral fractures did not differ between the two groups.
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Affiliation(s)
- Takeshi Mochizuki
- Department of Orthopedic Surgery, Kamagaya General Hospital, Kamagaya, Chiba, Japan.
| | - Koichiro Yano
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsunori Ikari
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Ken Okazaki
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
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16
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Shiraki M, Kuroda T, Nakano M, Nakamura Y, Saito M, Urano T. Nitric oxide is associated with fracture risk in Japanese women. PLoS One 2023; 18:e0280854. [PMID: 36749766 PMCID: PMC9904477 DOI: 10.1371/journal.pone.0280854] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 01/09/2023] [Indexed: 02/08/2023] Open
Abstract
Although nitric oxide (NO) is a known factor that regulates the bone physiology, few and discordant results have been obtained in human studies evaluating the effect of nitrates on bone health. We investigated for the relationship between serum NOx level and incident osteoporotic fracture rate prospectively in a cohort consisting of Japanese women. A total of 871 subjects (67.5 ± 10.8 y/o) were analyzed. During the observation period (8.8 ± 7.2 yrs), incident osteoporotic fractures occurred in 267 participants (209 vertebral fractures, 57 long-bone fractures, and 1 both types). Hazard ratio, by the Cox proportional hazards model, of serum NOx for incident fracture was 0.64 (95% confidence interval 0.53-0.78, p < 0.001) after adjustment for baseline age (1.13, 1.06-1.21, p < 0.001), lumbar bone mineral density (L-BMD; 0.85, 0.78-0.92, p < 0.001), presence of prevalent fracture (3.27, 2.49-4.32, p < 0.001), and treatment of osteoporosis (0.70, 0.53-0.92, p = 0.010). The relationships between serum level of NOx and bone-related parameters were examined by multiple regression analysis; body mass index (p < 0.001) and L-BMD (p = 0.011) were significantly associated with serum NOx level. These results suggest that the low circulating NOx is one of the independent predictors for osteoporotic fracture occurrence in postmenopausal women.
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Affiliation(s)
- Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, Azumino City, Nagano, Japan
| | | | - Masaki Nakano
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto City, Nagano, Japan
| | - Yukio Nakamura
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto City, Nagano, Japan
- * E-mail:
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Tomohiko Urano
- Department of Geriatric Medicine, International University of Health and Welfare School of Medicine, Narita City, Chiba, Japan
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17
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Brandt IAG, Jessen MH, Rimestad DE, Højgaard MKF, Vestergaard P. Advanced glycation end products and bone - How do we measure them and how do they correlate with bone mineral density and fractures? A systematic review and evaluation of precision of measures. Bone 2022; 165:116569. [PMID: 36174927 DOI: 10.1016/j.bone.2022.116569] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 08/20/2022] [Accepted: 09/21/2022] [Indexed: 11/24/2022]
Abstract
The role of advanced glycation end products (AGEs) in bone fragility especially in diabetic bone disease is increasingly recognized and researched. As skeletal frailty in diabetes does not correlate to bone mineral density (BMD) in the same way as in postmenopausal osteoporosis, BMD may not be a suitable measure of bone quality in persons with diabetes. Abundant research exists upon the effect of AGEs on bone, and though full understanding of the mechanisms of actions does not yet exist, there is little doubt of the clinical relevance. Thus, the measurement of AGEs as well as possible treatment effects on AGEs have become issues of interest. The aim of this report is to summarize results of measurements of AGEs. It consists of a systematic review of the existing literature on AGE measurements in clinical research, an evaluation of the precision of skin autofluorescence (SAF) measurement by AGE Reader® (Diagnoptics), and a short commentary on treatment of osteoporosis in patients with and without diabetes with respects to AGEs. We conclude that various AGE measures correlate well, both fluorescent and non-fluorescent and in different tissues, and that more than one target of measure may be used. However, pentosidine has shown good correlation with both bone measures and fracture risk in existing literature and results on SAF as a surrogate measurement is promising as some corresponding associations with fracture risk and bone measures are reported. As SAF measurements performed with the AGE Reader® display high precision and allow for a totally noninvasive procedure, conducting AGE measurements using this method has great potential and further research of its applicability is encouraged.
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18
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Vaidya R, Rezaee T, Edwards T, Bender R, Vickneswaran A, Chalivendra V, Karim L. Accumulation of fluorescent advanced glycation end products and carboxymethyl-lysine in human cortical and trabecular bone. Bone Rep 2022; 17:101634. [DOI: 10.1016/j.bonr.2022.101634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 11/06/2022] Open
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19
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Willett TL, Voziyan P, Nyman JS. Causative or associative: A critical review of the role of advanced glycation end-products in bone fragility. Bone 2022; 163:116485. [PMID: 35798196 PMCID: PMC10062699 DOI: 10.1016/j.bone.2022.116485] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 11/02/2022]
Abstract
The accumulation of advanced glycation end-products (AGEs) in the organic matrix of bone with aging and chronic disease such as diabetes is thought to increase fracture risk independently of bone mass. However, to date, there has not been a clinical trial to determine whether inhibiting the accumulation of AGEs is effective in preventing low-energy, fragility fractures. Moreover, unlike with cardiovascular or kidney disease, there are also no pre-clinical studies demonstrating that AGE inhibitors or breakers can prevent the age- or diabetes-related decrease in the ability of bone to resist fracture. In this review, we critically examine the case for a long-standing hypothesis that AGE accumulation in bone tissue degrades the toughening mechanisms by which bone resists fracture. Prior research into the role of AGEs in bone has primarily measured pentosidine, an AGE crosslink, or bulk fluorescence of hydrolysates of bone. While significant correlations exist between these measurements and mechanical properties of bone, multiple AGEs are both non-fluorescent and non-crosslinking. Since clinical studies are equivocal on whether circulating pentosidine is an indicator of elevated fracture risk, there needs to be a more complete understanding of the different types of AGEs including non-crosslinking adducts and multiple non-enzymatic crosslinks in bone extracellular matrix and their specific contributions to hindering fracture resistance (biophysical and biological). By doing so, effective strategies to target AGE accumulation in bone with minimal side effects could be investigated in pre-clinical and clinical studies that aim to prevent fragility fractures in conditions that bone mass is not the underlying culprit.
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Affiliation(s)
- Thomas L Willett
- Biomedical Engineering Program, Systems Design Engineering, University of Waterloo, Waterloo, Ontario, Canada.
| | - Paul Voziyan
- Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Jeffry S Nyman
- Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
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20
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Stephen SJ, Bailey S, D'Erminio DN, Krishnamoorthy D, Iatridis JC, Vashishth D. Bone matrix quality in a developing high-fat diet mouse model is altered by RAGE deletion. Bone 2022; 162:116470. [PMID: 35718325 PMCID: PMC9296598 DOI: 10.1016/j.bone.2022.116470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 06/07/2022] [Accepted: 06/07/2022] [Indexed: 11/20/2022]
Abstract
Overweightness and obesity in adolescents are epidemics linked to chronic low-grade inflammation and elevated fracture risk. The increased fracture risk observed in overweight/obese adolescence contrasts the traditional concept that high body mass is protective against fracture, and thus highlights the need to determine why weight gain becomes detrimental to fracture during growth and maturity. The Receptor for Advanced Glycation End products (RAGE) is a central inflammatory regulator that can influence bone metabolism. It remains unknown how RAGE removal impacts skeletal fragility in overweightness/obesity, and whether increased fracture risk in adolescents could result from low-grade inflammation deteriorating bone quality. We characterized the multiscale structural, mechanical, and chemical properties of tibiae extracted from adolescent C57BL/6J (WT) and RAGE null (KO) mice fed either low-fat (LF) or high-fat (HF) diet for 12 weeks starting at 6 weeks of age using micro-computed tomography, strength, Raman spectroscopy, and nanoindentation. Overweight/obese WT HF mice possessed degraded mineral-crystal quality and increased matrix glycoxidation in the form of pentosidine and carboxymethyl-lysine, with HF diet in females only showing reduced cortical surface expansion and TMD independently of RAGE ablation. Furthermore, in contrast to males, HF diet in females led to more material damage and plastic deformation. RAGE KO mitigated glycoxidative matrix accumulation, preserved mineral quantity, and led to increased E/H ratio in females. Taken together, these results highlight the complex, multi-scale and sex-dependent relationships between bone quality and function under overweightness, and identifies RAGE-controlled glycoxidation as a target to potentially preserve matrix quality and mechanical integrity.
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Affiliation(s)
- Samuel J Stephen
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Stacyann Bailey
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Danielle N D'Erminio
- Leni and Peter W. May Department of Orthopaedics, Ichan School of Medicine at Mount Sinai, New York, NY, USA
| | - Divya Krishnamoorthy
- Leni and Peter W. May Department of Orthopaedics, Ichan School of Medicine at Mount Sinai, New York, NY, USA
| | - James C Iatridis
- Leni and Peter W. May Department of Orthopaedics, Ichan School of Medicine at Mount Sinai, New York, NY, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute, Troy, NY, USA.
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21
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Taguchi A, Saito M, Shiraki M. Association of pentosidine and homocysteine levels with number of teeth present in Japanese postmenopausal women. J Bone Miner Metab 2022; 40:773-781. [PMID: 35697886 DOI: 10.1007/s00774-022-01343-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/11/2022] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Little is known about whether substances inducing tissue protein degeneration in the oral cavity are associated with the number of teeth present in postmenopausal women. We sought to investigate the association of urinary pentosidine and serum homocysteine levels with the number of teeth and subsequent tooth loss in Japanese postmenopausal women. MATERIALS AND METHODS Among participants in the Nagano Cohort Study, 785 postmenopausal women (mean age, 68.1 years) participated in the present study. The number of teeth was re-counted at the time of follow-up in 610 women. Poisson regression analysis was used to investigate differences in the number of teeth among quartiles of pentosidine or homocysteine, adjusting for covariates that correlated with the number of teeth. A Cox proportional hazard model was used to evaluate the association of subsequent tooth loss with pentosidine or homocysteine levels. RESULTS Pentosidine quartiles were not associated with the number of teeth at baseline. Participants in the highest homocysteine quartile had significantly fewer teeth at baseline than those in the third and lowest quartiles (p < 0.001 for both). Those in the second quartile had fewer teeth than those in the third (p = 0.001) and lowest (p < 0.001) quartiles. An increased risk of tooth loss during follow-up was significantly associated with higher urinary pentosidine (hazard ratio = 1.073 for 10 pmol/mgCre; p = 0.001). CONCLUSION Postmenopausal women with higher homocysteine levels had fewer teeth at baseline. A higher pentosidine concentration increased the risk of subsequent tooth loss. High pentosidine or homocysteine concentrations may be associated with tooth loss in postmenopausal women.
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Affiliation(s)
- Akira Taguchi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano, 399-0781, Japan.
- Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano, 399-0781, Japan.
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-19-18 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8471, Japan
| | - Masataka Shiraki
- Department of Internal Medicine, Research Institute and Practice for Involutional Diseases, 1610-1 Meisei, Misato, Azumino, Nagano, 399-8101, Japan
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22
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Tanaka S, Saito M, Hagino H, Mori S, Nakamura T, Ohta H, Sone T, Takahashi K, Mitomo Y, Sugimoto T, Soen S. Association of urinary pentosidine levels with the risk of fractures in patients with severe osteoporosis: the Japanese Osteoporosis Intervention Trial‐05 (JOINT‐‐05). JBMR Plus 2022; 6:e10673. [PMID: 36248273 PMCID: PMC9549726 DOI: 10.1002/jbm4.10673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/14/2022] [Accepted: 08/08/2022] [Indexed: 11/10/2022] Open
Affiliation(s)
- Shiro Tanaka
- Department of Clinical Biostatistics Graduate School of Medicine Kyoto University, Yoshida Konoe‐cho, Sakyo‐ku Kyoto Japan
| | - Mitsuru Saito
- Department of Orthopedic Surgery Jikei University School of Medicine, 3‐25‐8 Nishi‐Shimbashi, Minato‐ku Tokyo Japan
| | - Hiroshi Hagino
- School of Health Sciences, Tottori University Faculty of Medicine, Nishicho, Yonago Tottori Japan
| | - Satoshi Mori
- Seirei Hamamatsu General Hospital, Sumiyoshi, Naka‐ku, Hamamatsu Shizuoka Japan
| | - Toshitaka Nakamura
- Touto Sangenjaya Rehabilitation Hospital, 1‐24‐3 Sangenjaya, Setagaya‐ku Tokyo Japan
| | - Hiroaki Ohta
- Department of Obstetrics and Gynecology Kawasaki Medical School General Medical Center, 2‐6‐1 Nakasange, Kita‐ku Okayama Japan
| | - Teruki Sone
- Department of Nuclear Medicine Kawasaki Medical School, 577 Matsushima, Kurashiki Okayama Japan
| | - Kaito Takahashi
- Department of Clinical Biostatistics Graduate School of Medicine Kyoto University, Yoshida Konoe‐cho, Sakyo‐ku Kyoto Japan
| | - Yuji Mitomo
- Department of Clinical Biostatistics Graduate School of Medicine Kyoto University, Yoshida Konoe‐cho, Sakyo‐ku Kyoto Japan
| | | | - Satoshi Soen
- Soen Orthopaedics, Osteoporosis and Rheumatology Clinic, 2‐14‐10 Okamoto, Higashinada‐ku Kobe‐shi Hyogo Japan
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23
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The association between urinary pentosidine levels and cognition in drug-naïve patients with Parkinson’s disease. Neurol Sci 2022; 43:6323-6328. [DOI: 10.1007/s10072-022-06332-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/08/2022] [Indexed: 11/26/2022]
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24
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Sroga GE, Stephen S, Wang B, Vashishth D. Techniques for advanced glycation end product measurements for diabetic bone disease: pitfalls and future directions. Curr Opin Endocrinol Diabetes Obes 2022; 29:333-342. [PMID: 35777968 PMCID: PMC9348815 DOI: 10.1097/med.0000000000000736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Multiple biochemical and biophysical approaches have been broadly used for detection and quantitation of posttranslational protein modifications associated with diabetic bone, yet these techniques present a variety of challenges. In this review, we discuss recent advancements and complementary roles of analytical (UPLC/UPLC-MS/MS and ELISA) and biophysical (Raman and FTIR) techniques used for characterization of glycation products, measured from bone matrix and serum, and provide recommendations regarding the selection of a technique for specific study of diabetic bone. RECENT FINDINGS Hyperglycemia and oxidative stress in diabetes contribute to the formation of a large subgroup of advanced glycation end products (AGEs) known as glycoxidation end products (AGOEs). AGEs/AGOEs have various adverse effects on bone health. Commonly, accumulation of AGEs/AGOEs leads to increased bone fragility. For example, recent studies show that carboxymethyllysine (CML) and pentosidine (PEN) are formed in bone at higher levels in certain diseases and metabolic conditions, in particular, in diabetes and aging. Detection and quantitation of AGEs/AGOEs in rare and/or precious samples is feasible because of a number of technological advancements of the past decade. SUMMARY Recent technological advancements have led to a significant improvement of several key analytical biochemistry and biophysics techniques used for detection and characterization of AGEs/AGOEs in bone and serum. Their principles and applications to skeletal tissue studies as well as limitations are discussed in this review.
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Affiliation(s)
- Grażyna E. Sroga
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Samuel Stephen
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Bowen Wang
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
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Dhaliwal R, Ewing SK, Vashishth D, Semba RD, Schwartz AV. Greater Carboxy-Methyl-Lysine Is Associated With Increased Fracture Risk in Type 2 Diabetes. J Bone Miner Res 2022; 37:265-272. [PMID: 34820902 PMCID: PMC8828668 DOI: 10.1002/jbmr.4466] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/20/2021] [Accepted: 10/02/2021] [Indexed: 02/06/2023]
Abstract
Accumulation of advanced glycation end-products (AGE) in bone alters collagen structure and function. Fluorescent AGEs are associated with fractures but less is known regarding non-fluorescent AGEs. We examined associations of carboxy-methyl-lysine (CML), with incident clinical and prevalent vertebral fractures by type 2 diabetes (T2D) status, in the Health, Aging, and Body Composition cohort of older adults. Incident clinical fractures and baseline vertebral fractures were assessed. Cox regression was used to analyze the associations between serum CML and clinical fracture incidence, and logistic regression for vertebral fracture prevalence. At baseline, mean ± standard deviation (SD) age was 73.7 ± 2.8 and 73.6 ± 2.9 years in T2D (n = 712) and non-diabetes (n = 2332), respectively. Baseline CML levels were higher in T2D than non-diabetes (893 ± 332 versus 771 ± 270 ng/mL, p < 0.0001). In multivariate models, greater CML was associated with higher risk of incident clinical fracture in T2D (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.24-1.79 per 1-SD increase in log CML) but not in non-diabetes (HR 1.03; 95% CI, 0.94-1.13; p for interaction = 0.001). This association was independent of bone mineral density (BMD), glycated hemoglobin (hemoglobin A1c), weight, weight loss, smoking, cystatin-C, and medication use. CML was not significantly associated with the odds of prevalent vertebral fractures in either group. In conclusion, higher CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. These results implicate CML in the pathogenesis of bone fragility in diabetes. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Ruban Dhaliwal
- Metabolic Bone Disease Center, State University of New York Upstate Medical University, New York, NY, USA
| | - Susan K. Ewing
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, New York, NY, USA
| | - Richard D. Semba
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ann V. Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
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Tice MJ, Bailey S, Sroga GE, Gallagher EJ, Vashishth D. Non‐Obese
MKR
Mouse Model of Type 2 Diabetes Reveals Skeletal Alterations in Mineralization and Material Properties. JBMR Plus 2021; 6:e10583. [PMID: 35229063 PMCID: PMC8861985 DOI: 10.1002/jbm4.10583] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/15/2021] [Accepted: 11/14/2021] [Indexed: 12/25/2022] Open
Abstract
Obesity is a common comorbidity of type 2 diabetes (T2D). Therefore, increased risk of fragility fractures in T2D is often confounded by the effects of obesity. This study was conducted to elucidate the mechanistic basis by which T2D alone leads to skeletal fragility. We hypothesized that obesity independent T2D would deteriorate bone's material quality by accumulating defects in the mineral matrix and undesired modifications in its organic matrix associated with increased oxidative stress and hyperglycemia. To test this hypothesis, we used 15‐week‐old male non‐obese mice with engineered muscle creatine kinase promoter/human dominant negative insulin growth factor 1 (IGF‐I) receptor (MKR) and FVB/N wild‐type (WT) controls (n = 12/group). MKR mice exhibit reduced insulin production and loss of glycemic control leading to diabetic hyperglycemia, verified by fasting blood glucose measurements (>250 mg/dL), without an increase in body weight. MKR mice showed a significant decrease in femoral radial geometry (cortical area, moment of inertia, cortical thickness, endosteal diameter, and periosteal diameter). Bone mineral density (BMD), as assessed by micro–computed tomography (μCT), remained unchanged; however, the quality of bone mineral was altered. In contrast to controls, MKR mice had significantly increased hydroxyapatite crystal thickness, measured by small‐angle X‐ray scattering, and elongated c‐axis length of the crystals evaluated by confocal Raman spectroscopy. There was an increase in changes in the organic matrix of MKR mice, associated with enhanced glycoxidation (carboxymethyl‐lysine [CML] and pentosidine) and overall glycation (fluorescent advanced glycation end products), both of which were associated with various measures of bone fragility. Moreover, increased CML formation positively correlated with elongated mineral crystal length, supporting the role of this negatively charged side chain to attract calcium ions, promote growth of hydroxyapatite, and build a physical link between mineral and collagen. Collectively, our results show, for the first time, changes in bone matrix in a non‐obese T2D model in which skeletal fragility is attributable to alterations in the mineral quality and undesired organic matrix modifications. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Matthew J.L. Tice
- Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA
| | - Stacyann Bailey
- Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA
| | - Grażyna E. Sroga
- Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA
| | - Emily J. Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA
| | - Deepak Vashishth
- Department of Biomedical Engineering Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute New York NY USA
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Tahara N, Tahara A, Maeda-Ogata S, Yoshimura H, Bekki M, Sugiyama Y, Honda A, Igata S, Nishino Y, Matsui T, Fukami A, Enomoto M, Adachi H, Fukumoto Y, Yamagishi SI. Increased Urinary Levels of Pentosidine Measured by a Newly Developed Enzyme-Linked Immunosorbent Assay Are Independently Correlated with Fracture After Fall. Rejuvenation Res 2021; 24:449-455. [PMID: 34846174 DOI: 10.1089/rej.2021.0066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Although we have found that increased serum levels of glyceraldehyde-derived advanced glycation end products (AGEs) are associated with numerous aging-related disorders, it remains unclear which structurally distinct AGEs could be a reliable biomarker of the healthy life-threatening disorders. Since pentosidine is produced by glyceraldehyde, we measured here urinary pentosidine levels with a newly developed enzyme-linked immunosorbent assay (ELISA) kit, which requires no pretreatment with acid hydrolysis and heat, and examined their correlations with geriatric syndrome, such as musculoskeletal disease, frailty, and cognitive impairment, in a general population. Multiple regression analysis revealed that female, age, history of fracture after fall, and taking medication for diabetes were independent correlates of log urine pentosidine-to-creatinine ratio (R2 = 0.190). When gender-adjusted log urine pentosidine-to-creatinine ratio stratified by smile frequency grade was compared using analysis of covariance, urine pentosidine-to-creatinine ratio was significantly decreased according to the increase in smile frequency. Our present findings suggest that measurement of urine pentosidine-to-creatinine ratio by a newly developed ELISA kit may be useful for identifying high-risk patients for fall-related fractures.
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Affiliation(s)
- Nobuhiro Tahara
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Atsuko Tahara
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shoko Maeda-Ogata
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hanae Yoshimura
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Munehisa Bekki
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yoichi Sugiyama
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Akihiro Honda
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Sachiyo Igata
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yuri Nishino
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Takanori Matsui
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Ako Fukami
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Mika Enomoto
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hisashi Adachi
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yoshihiro Fukumoto
- Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Sho-Ichi Yamagishi
- Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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Nakano M, Nakamura Y, Urano T, Miyazaki A, Suzuki T, Watanabe K, Takahashi J, Shiraki M. Associations of Homocysteine Metabolism With the Risk of Spinal Osteoarthritis Progression in Postmenopausal Women. J Clin Endocrinol Metab 2021; 106:3428-3438. [PMID: 34375425 DOI: 10.1210/clinem/dgab591] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Indexed: 02/07/2023]
Abstract
CONTEXT Although homocysteine accumulation is a reported risk factor for several age-related disorders, little is known about its relationship with osteoarthritis (OA). OBJECTIVE We investigated for associations of homocysteine and C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR), which is involved in homocysteine clearance, with the development and progression of spinal OA through a combined cross-sectional and longitudinal cohort study. METHODS A total of 1306 Japanese postmenopausal outpatients participating in the Nagano Cohort Study were followed for a mean 9.7-year period. Cross-sectional multiple logistic regression for spinal OA prevalence at registration by serum homocysteine level was performed with adjustment for confounders. In addition to Kaplan-Meier analysis, multivariate Cox regression was employed to examine the independent risk of MTHFR C677T variant for spinal OA progression. RESULTS Multivariate regression analysis revealed a significant association between homocysteine and spinal OA prevalence (odds ratio 1.38; 95% CI 1.14-1.68). Kaplan-Meier curves showed a gene dosage effect of the T allele in MTHFR C677T polymorphism on the accelerated progression of spinal OA severity (P = 0.003). A statistically significant independent risk of the T allele for spinal OA advancement was validated by Cox regression analysis. Respective adjusted hazard ratios for the CT/TT and TT genotypes were 1.68 (95% CI, 1.16-2.42) and 1.67 (95% CI, 1.23-2.28). CONCLUSION Circulating homocysteine and C677T variant in MTHFR are associated with the prevalence rate and ensuing progression, respectively, of spinal OA. These factors may represent potential interventional targets to prevent OA development and improve clinical outcomes.
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Affiliation(s)
- Masaki Nakano
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Yukio Nakamura
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Tomohiko Urano
- Department of Geriatric Medicine, International University of Health and Welfare School of Medicine, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan
| | - Akiko Miyazaki
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Takako Suzuki
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
- Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, 22 Sanban-cho, Chiyoda-ku, Tokyo 102-8341, Japan
| | - Kazuki Watanabe
- Department of Biology, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, 2-8-30 Kohnodai, Ichikawa, Chiba 272-0827, Japan
| | - Jun Takahashi
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, 1610-1 Meisei, Misato, Azumino, Nagano 399-8101, Japan
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Каландия ММ, Токмакова АЮ, Галстян ГР. [The role of glycation end products in the development and progression of diabetic neuroarthropathy]. PROBLEMY ENDOKRINOLOGII 2021; 67:4-9. [PMID: 34297497 PMCID: PMC9112848 DOI: 10.14341/probl12778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/04/2021] [Accepted: 07/04/2021] [Indexed: 12/16/2022]
Abstract
Diabetic neuroarthropathy (DNOAP, Charcot's foot) is a serious complication of diabetes mellitus, the genesis of which is not fully understood. In most cases, this pathology is diagnosed late, which leads to the development of severe deformities of the foot, up to the loss of support ability of the limb. There is no single hypothesis for the formation of Charcot's foot, but there are factors predisposing to its development, as well as a few likely provoking events. Excessive formation and accumulation of end products of glycation may play an important role in the pathogenesis of this complication of diabetes. End products of glycation (AGE) are a variety of compounds formed as a result of a non-enzymatic reaction between carbohydrates and free amino groups of proteins, lipids and nucleic acids. There are various factors that lead to the accumulation of AGE in the human body. Allocate endogenous and exogenous factors. The former include certain diseases, such as diabetes mellitus, renal failure, which accelerate glycation processes. Exogenous factors leading to the formation of lipo-oxidation and glyco-oxidation products include tobacco smoke and prolonged heat treatment of food.This review provides information on the role of glycation end products in the development and progression of complications in patients with diabetes mellitus.
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Affiliation(s)
- М. М. Каландия
- Национальный медицинский исследовательский центр эндокринологии
| | - А. Ю. Токмакова
- Национальный медицинский исследовательский центр эндокринологии
| | - Г. Р. Галстян
- Национальный медицинский исследовательский центр эндокринологии
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Moriwaki K, Matsumoto H, Tanimura C, Osaki M, Nagashima H, Hagino H. Urinary pentosidine level is associated with grip strength and gait speed in community-dwelling adults: a cross-sectional study. BMC Musculoskelet Disord 2021; 22:392. [PMID: 33902533 PMCID: PMC8077690 DOI: 10.1186/s12891-021-04279-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 04/20/2021] [Indexed: 01/22/2023] Open
Abstract
Background Muscle and bone interactions might be associated with osteoporosis and sarcopenia. Urinary pentosidine and serum 25-hydroxyvitamin D (25(OH)D) might affect muscle and bone interactions. It is unclear whether these biomarkers are affected by age and sex or play a role in muscle and physical functions. We aimed to investigate the association between urinary pentosidine and serum 25(OH)D levels with muscle mass, muscle strength, and physical performance in community-dwelling adults. Methods Two-hundred and fifty-four middle-aged and elderly adults were enrolled. There was no significant difference in age between 97 men (75.0 ± 8.9 years) and 157 women (73.6 ± 8.1 years). The skeletal muscle mass index (SMI), grip strength, and gait speed were assessed. The urinary pentosidine level was measured. We evaluated the association of urinary pentosidine and serum 25(OH)D levels with age and sex (student’s t-test) and correlations between biomarker and each variable (Pearson’s correlation coefficients). Multiple regression analysis was performed with grip strength and gait speed as dependent variables and with age, height, weight, body mass index (BMI), speed of sound (SOS), SMI, glycated hemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), 25(OH)D, and pentosidine as independent variables using the stepwise method. Results The urinary pentosidine level was negatively correlated with grip strength, gait speed, eGFR, and insulin-like growth factor-1 (IGF-1) in men and with SOS, grip strength, and gait speed in women. The serum 25(OH)D level was positively correlated with IGF-1 in women and grip strength in men. Grip strength was associated with age, height, and pentosidine in men and height and pentosidine in women. Gait speed was associated with age, BMI, and pentosidine in men and age, height, and pentosidine in women. Conclusion Urinary pentosidine levels are significantly associated with grip strength and gait speed and may serve as a biomarker of muscle and bone interactions.
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Affiliation(s)
- Kenta Moriwaki
- Department of Orthopedic Surgery, Faculty of Medicine, Tottori University, Nishicho 36-1, Yonago, Tottori, 683-8504, Japan. .,Department of Orthopedic Surgery, Misasa Onsen Hospital, Yamada 690Misasa, Tottori, 682-0122, Japan.
| | - Hiromi Matsumoto
- Department of Rehabilitation, Faculty of Health Science and Technology, Kawasaki University of Medical Welfare, Matsushima 288, Kurashiki, Okayama, 701-0193, Japan
| | - Chika Tanimura
- School of Health Science, Faculty of Medicine, Tottori University, Nishicho 86, Yonago, Tottori, 683-8504, Japan
| | - Mari Osaki
- Rehabilitation Division, Tottori University Hospital, Nishicho 36-1, Yonago, Tottori, 683-8504, Japan
| | - Hideki Nagashima
- Department of Orthopedic Surgery, Faculty of Medicine, Tottori University, Nishicho 36-1, Yonago, Tottori, 683-8504, Japan
| | - Hiroshi Hagino
- School of Health Science, Faculty of Medicine, Tottori University, Nishicho 86, Yonago, Tottori, 683-8504, Japan.,Rehabilitation Division, Tottori University Hospital, Nishicho 36-1, Yonago, Tottori, 683-8504, Japan
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Tominaga A, Wada K, Kato Y, Nishi H, Terayama Y, Okazaki K. Early clinical effects, safety, and appropriate selection of bone markers in romosozumab treatment for osteoporosis patients: a 6-month study. Osteoporos Int 2021; 32:653-661. [PMID: 32979066 DOI: 10.1007/s00198-020-05639-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/11/2020] [Indexed: 01/22/2023]
Abstract
UNLABELLED Our 6-month study showed the usefulness of romosozumab for preventing fractures and its safety. It was effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP. Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with that from baseline of BMD after four to 6-month treatment. INTRODUCTION Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody which increases bone formation and suppresses bone resorption. In this study, we analyzed the actual clinical effects, adverse effects, and the optimal way to evaluate the treatment. METHODS Romosozumab was administered as subcutaneous injection of 210 mg once every 4 weeks. We conducted pre-post study in 185 patients treated for 6 months. We focused on the incidence of new vertebral fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. We evaluated BMD before romosozumab treatment and after 4 to 6 months and performed the serum analysis before romosozumab treatment, after 1, 3, and 6 months. RESULTS There was no new fracture during treatment, and there was no fatal adverse event including cardiovascular disease. Since percent changes from baseline of the spine and total hip BMD were 6.34% and 1.53% after 4- to 6-month treatment, the treatment was effective for spine osteoporosis. Tartrate-resistant acid phosphatase 5b (TRACP-5b) and intact type I procollagen N-terminal propeptide (iP1NP) had significant changes during romosozumab treatment (p < 0.05). Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with percent change from baseline of BMD after 4 to 6 months of treatment. CONCLUSION Romosozumab is effective in preventing fractures and useful for increasing the spine BMD. Also, romosozumab is relatively safe to use. It is especially effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP.
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Affiliation(s)
- A Tominaga
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - K Wada
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan.
| | - Y Kato
- Kita Shinagawa 3rd Hospital, Tokyo, Japan
| | - H Nishi
- Hasuda Hospital, Saitama, Japan
| | | | - K Okazaki
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
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Pentosidine and carboxymethyl-lysine associate differently with prevalent osteoporotic vertebral fracture and various bone markers. Sci Rep 2020; 10:22090. [PMID: 33328494 PMCID: PMC7744574 DOI: 10.1038/s41598-020-78993-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/30/2020] [Indexed: 02/08/2023] Open
Abstract
Pentosidine (PEN) and carboxymethyl-lysine (CML) are well-recognized advanced glycation end products (AGEs). However, how these AGEs affect the pathophysiology of osteoporosis and osteoporotic fractures remains controversial. This cross-sectional study aimed to investigate the associations of PEN and CML with bone markers, bone mineral density (BMD), and osteoporotic fractures in postmenopausal women from the Nagano Cohort Study. A total of 444 Japanese postmenopausal outpatients (mean ± standard deviation age: 69.8 ± 10.2 years) were enrolled after the exclusion of patients with acute or severe illness or secondary osteoporosis. The relationships among urinary PEN and serum CML levels, various bone markers, lumbar and hip BMD, and prevalent vertebral and long-bone fractures were evaluated. PEN associated significantly with prevalent vertebral fracture after adjustment for other confounders (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.22-2.07; P < 0.001), but not with lumbar BMD. In contrast, a significant negative correlation was found between CML and lumbar BMD (r = - 0.180; P < 0.001), and this relationship was significant after adjustment for confounders (OR 0.84, 95% CI 0.76-0.93; P < 0.01). Although patients with prevalent vertebral fracture had significantly higher CML levels, the association between CML and prevalent vertebral fracture did not reach significance in the multivariate regression model. Both PEN and CML may play important roles in bone health for postmenopausal women, possibly via different mechanisms.
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Arakawa S, Suzuki R, Kurosaka D, Ikeda R, Hayashi H, Kayama T, Ohno RI, Nagai R, Marumo K, Saito M. Mass spectrometric quantitation of AGEs and enzymatic crosslinks in human cancellous bone. Sci Rep 2020; 10:18774. [PMID: 33139851 PMCID: PMC7606603 DOI: 10.1038/s41598-020-75923-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023] Open
Abstract
Advanced glycation end-products (AGEs) deteriorate bone strength. Among over 40 species identified in vivo, AGEs other than pentosidine were roughly estimated as total fluorescent AGEs (tfAGEs) due to technical difficulties. Using LC-QqTOF-MS, we established a system that enabled the quantitation of five AGEs (CML, CEL, MG-H1, CMA and pentosidine) as well as two mature and three immature enzymatic crosslinks. Human bone samples were collected from 149 patients who underwent total knee arthroplasty. Their clinical parameters were collected to investigate parameters that may be predictive of AGE accumulation. All the analytes were quantitated and showed significant linearity with high sensitivity and precision. The results showed that MG-H1 was the most abundant AGE, whereas pentosidine was 1/200-1/20-fold less abundant than the other four AGEs. The AGEs were significantly and strongly correlated with pentosidine, while showing moderate correlation with tfAGEs. Interestingly, multiple linear regression analysis revealed that gender contributed most to the accumulation of all the AGEs, followed by age, tartrate-resistant acid phosphatase-5b and HbA1c. Furthermore, the AGEs were negatively correlated with immature crosslinks. Mass spectrometric quantitation of AGEs and enzymatic crosslinks is crucial to a better understanding of ageing- and disease-related deterioration of bone strength.
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Affiliation(s)
- Shoutaro Arakawa
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
- Laboratory of Food and Regulation Biology, School of Agriculture, Tokai University, 9-1-1, Toroku, Higashi-ku, Kumamoto, 862-8652, Japan.
| | - Ryusuke Suzuki
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
- Laboratory of Food and Regulation Biology, School of Agriculture, Tokai University, 9-1-1, Toroku, Higashi-ku, Kumamoto, 862-8652, Japan
| | - Daisaburo Kurosaka
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Ryo Ikeda
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Hiroteru Hayashi
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Tomohiro Kayama
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Rei-Ichi Ohno
- Laboratory of Food and Regulation Biology, School of Agriculture, Tokai University, 9-1-1, Toroku, Higashi-ku, Kumamoto, 862-8652, Japan
| | - Ryoji Nagai
- Laboratory of Food and Regulation Biology, School of Agriculture, Tokai University, 9-1-1, Toroku, Higashi-ku, Kumamoto, 862-8652, Japan
| | - Keishi Marumo
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
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Uemura Y, Sone T, Tanaka S, Miyazaki T, Tsukiyama M, Taguchi A, Soen S, Mori S, Hagino H, Sugimoto T, Fukunaga M, Ohta H, Nakamura T, Orimo H, Shiraki M. Randomized head-to-head comparison of minodronic acid and raloxifene for fracture incidence in postmenopausal Japanese women: the Japanese Osteoporosis Intervention Trial (JOINT)-04. Curr Med Res Opin 2020; 36:1847-1859. [PMID: 32870712 DOI: 10.1080/03007995.2020.1816537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
AIMS We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety. METHODS The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients' quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433. RESULTS A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78-1.13, p = .494), 0.86 (95% CI: 0.70-1.05, p = .147), and 1.22 (95% CI: 0.86-1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p<.0001). Also, serious adverse reactions were observed for four and six patients in the minodronate and raloxifene groups, respectively. CONCLUSIONS Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.
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Affiliation(s)
- Yukari Uemura
- Department of Data Science, Biostatistics Section, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Teruki Sone
- Department of Nuclear Medicine, Kawasaki Medical School, Okayama, Japan
| | - Shiro Tanaka
- Department of Clinical Biostatistics, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | | | | | - Akira Taguchi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Matsumoto Dental University, Nagano, Japan
| | - Satoshi Soen
- Department of Orthopaedic Surgery and Rheumatology, Nara Hospital, Kindai University, Nara, Japan
| | - Satoshi Mori
- Bone and Joint Surgery, Seirei Hamamatu General Hospital, Shizuoka, Japan
| | - Hiroshi Hagino
- School of Health Science, Tottori University faculty of Medicine, Tottori, Japan
| | | | - Masao Fukunaga
- Department of Nuclear Medicine, Kawasaki Medical School, Okayama, Japan
| | - Hiroaki Ohta
- International Medical Center, Fujita Health University, Aichi, Japan
| | | | | | - Masataka Shiraki
- Department of Internal Medicine, Research Institute and Practice for Involutional Diseases, Nagano, Japan
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Naffa R, Gaar J, Zhang W, Maidment C, Shehadi I, Etxabide A, Holmes G, Kavianinia I, Brimble M. Rapid and simultaneous analysis of advanced glycation end products on silica hydride column: Comparison of ultraviolet, fluorescence, and mass spectrometry detectors. SEPARATION SCIENCE PLUS 2020. [DOI: 10.1002/sscp.202000077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Rafea Naffa
- NZ Leather and Shoe Research Association (LASRA®) Palmerston North New Zealand
| | - Jakob Gaar
- School of Chemical Sciences University of Auckland Auckland New Zealand
| | - Wenkai Zhang
- NZ Leather and Shoe Research Association (LASRA®) Palmerston North New Zealand
| | - Catherine Maidment
- NZ Leather and Shoe Research Association (LASRA®) Palmerston North New Zealand
| | - Ihsan Shehadi
- College of Science Department of Chemistry University of Sharjah Sharjah UAE
| | - Alaitz Etxabide
- School of Chemical Sciences University of Auckland Auckland New Zealand
- ALITEC Research Group Department of Agronomy Biotechnology and Food School of Agricultural Engineering Public University of Navarre (upna/nup) Pamplona‐Iruña Spain
| | - Geoff Holmes
- NZ Leather and Shoe Research Association (LASRA®) Palmerston North New Zealand
| | - Iman Kavianinia
- School of Chemical Sciences University of Auckland Auckland New Zealand
| | - Margaret Brimble
- School of Chemical Sciences University of Auckland Auckland New Zealand
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Waqas K, Chen J, Koromani F, Trajanoska K, van der Eerden BC, Uitterlinden AG, Rivadeneira F, Zillikens MC. Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study. J Bone Miner Res 2020; 35:1904-1913. [PMID: 32463533 PMCID: PMC7687120 DOI: 10.1002/jbmr.4096] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 04/16/2020] [Accepted: 05/10/2020] [Indexed: 02/06/2023]
Abstract
Advanced glycation end-products (AGEs), which bind to type 1 collagen in bone and skin, have been implicated in reduced bone quality. The AGE reader™ measures skin autofluorescence (SAF), which might be regarded as a marker of long-term accumulation of AGEs in tissues. We investigated the association of SAF with bone mineral density (BMD) and fractures in the general population. We studied 2853 individuals from the Rotterdam Study with available SAF measurements (median age, 74.1 years) and with data on prevalent major osteoporotic (MOFs: hip, humerus, wrist, clinical vertebral) and vertebral fractures (VFs: clinical + radiographic Genant's grade 2 and 3). Radiographs were assessed 4 to 5 years before SAF. Multivariate regression models were performed adjusted for age, sex, BMI, creatinine, smoking status, and presence of diabetes and additionally for BMD with interaction terms to test for effect modification. Prevalence of MOFs was 8.5% and of VFs 7%. SAF had a curvilinear association with prevalent MOFs and VFs and therefore, age-adjusted, sex stratified SAF quartiles were used. The odds ratio (OR) (95% confidence interval [CI]) of the second, third and fourth quartiles of SAF for MOFs were as follows: OR 1.60 (95% CI, 1.08-2.35; p = .02); OR 1.30 (95% CI, 0.89-1.97; p = .20), and OR 1.40 (95% CI, 0.95-2.10; p = .09), respectively, with first (lowest) quartile as reference. For VFs the ORs were as follows: OR 1.69 (95% CI, 1.08-2.64; p = .02), OR 1.74(95% CI, 1.11-2.71; p = .01), and OR 1.73 (95% CI, 1.12-2.73; p = .02) for second, third, and fourth quartiles, respectively. When comparing the top three quartiles combined with the first quartile, the OR (95% CI) for MOFs was 1.43 (95% CI, 1.04-2.00; p = .03) and for VFs was 1.72 (95% CI, 1.18-2.53; p = .005). Additional adjustment for BMD did not change the associations. In conclusion, there is evidence of presence of a threshold of skin AGEs below which there is distinctly lower prevalence of fractures. Longitudinal analyses are needed to confirm our cross-sectional findings. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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Affiliation(s)
- Komal Waqas
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jinluan Chen
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Fjorda Koromani
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Katerina Trajanoska
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Bram Cj van der Eerden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - André G Uitterlinden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Fernando Rivadeneira
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M Carola Zillikens
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
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Suzuki A, Yabu A, Nakamura H. Advanced glycation end products in musculoskeletal system and disorders. Methods 2020; 203:179-186. [PMID: 32987130 DOI: 10.1016/j.ymeth.2020.09.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/18/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
The human population is ageing globally, and the number of old people is increasing yearly. Diabetes is common in the elderly, and the number of diabetic patients is also increasing. Elderly and diabetic patients often have musculoskeletal disorder, which are associated with advanced glycation end products (AGEs). AGEs are heterogeneous molecules derived from non-enzymatic products of the reaction of glucose or other sugar derivatives with proteins or lipids, and many different types of AGEs have been identified. AGEs are a biomarker for ageing and for evaluating disease conditions. Fluorescence, spectroscopy, mass spectrometry, chromatography, and immunological methods are commonly used to measure AGEs, but there is no standardized evaluation method because of the heterogeneity of AGEs. The formation of AGEs is irreversible, and they accumulate in tissue, eventually causing damage. AGE accumulation has been confirmed in neuromusculoskeletal tissues, including bones, cartilage, muscles, tendons, ligaments, and nerves, where they adversely affect biomechanical properties by causing charge changes and forming cross-linkages. AGEs also bind to receptors, such as the receptor for AGEs (RAGE), and induce inflammation by intracellular signal transduction. These mechanisms cause many varied aging and diabetes-related pathological conditions, such as osteoporosis, osteoarthritis, sarcopenia, tendinopathy, and neuropathy. Understanding of AGEs related pathomechanism may lead to develop novel methods for the prevention and therapy of such disorders which affect patients' quality of life. Herein, we critically review the current methodology used for detecting AGEs, and present potential mechanisms by which AGEs cause or exacerbate musculoskeletal disorders.
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Affiliation(s)
- Akinobu Suzuki
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan.
| | - Akito Yabu
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan
| | - Hiroaki Nakamura
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan
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Saeki C, Saito M, Oikawa T, Nakano M, Torisu Y, Saruta M, Tsubota A. Effects of denosumab treatment in chronic liver disease patients with osteoporosis. World J Gastroenterol 2020; 26:4960-4971. [PMID: 32952342 PMCID: PMC7476181 DOI: 10.3748/wjg.v26.i33.4960] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease (CLD) patients. Denosumab has been shown to increase bone mineral density (BMD) and decrease the risk of osteoporotic fracture in the general population. However, there are few reports evaluating the efficacy of denosumab in CLD patients.
AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.
METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo. The study period for evaluating efficacy and safety was 12 mo. Changes from baseline in BMD at the lumbar spine, femoral neck, and total hip were evaluated at 12 mo of denosumab treatment. Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b (bone resorption marker), serum total procollagen type I N-terminal propeptide (bone formation maker), and plasma pentosidine (bone quality marker).
RESULTS Among the 405 CLD patients, 138 (34.1%) patients were diagnosed with osteoporosis; among these, 78 patients met the exclusion criteria and thus 60 patients were finally included in the present study. The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine, femoral neck, and total hip were +4.44%, +3.71%, and +4.03%, respectively. Denosumab significantly improved BMD, regardless of sex, patient age, and presence of liver cirrhosis. Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment (P < 0.001). Plasma pentosidine levels were also significantly lower at 12 mo of treatment (P = 0.010). No patients experienced fractures and moderate-to-severe adverse events, except for transient hypocalcemia.
CONCLUSION Denosumab treatment was safe and increased BMD, suppressed bone turnover, and improved bone quality marker levels in CLD patients with osteoporosis, irrespective of differences in baseline characteristics.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo 1058461, Japan
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Nakamura Y, Nakano M, Suzuki T, Sato J, Kato H, Takahashi J, Shiraki M. Two adipocytokines, leptin and adiponectin, independently predict osteoporotic fracture risk at different bone sites in postmenopausal women. Bone 2020; 137:115404. [PMID: 32360897 DOI: 10.1016/j.bone.2020.115404] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/20/2020] [Accepted: 04/28/2020] [Indexed: 01/09/2023]
Abstract
Although associations among obesity, adipocytokines, and bone mineral density have been reported, the influence of adipocytokines on osteoporotic fractures remains unclear. This study aimed to assess the impact of the adipocytokines leptin and adiponectin on the risk of incident vertebral and long-bone fractures in postmenopausal women. Clinical data were obtained from the retrospective Nagano Cohort Study of outpatients followed at a single primary care institute in Nagano Prefecture, Japan, between 1993 and 2018. The primary outcome was the occurrence of incident vertebral or long-bone fractures. In total, 1167 Japanese postmenopausal women (mean age: 65.9 years) completed the follow-up and the average observation period was 7.2 years. The subjects were divided into 4 groups (quartile 1 to 4) based respective leptin and adiponectin values. Kaplan-Meier analysis demonstrated a significantly lower incident long-bone fracture rate in the higher quartiles of serum leptin levels (p = 0.002). A significantly higher and more rapid occurrence of incident vertebral fractures, but not long-bone fractures, was found in the highest adiponectin quartile (p < 0.001). A Cox proportional hazards model adjusted for confounders including age, body weight, and either leptin or adiponectin revealed lower leptin levels and higher adiponectin levels as significant independent risk factors for incident long-bone fractures (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.50-0.96; p = 0.03) and vertebral fractures (HR 1.18, 95% CI 1.02-1.37; p = 0.02), respectively. Therefore, serum leptin and adiponectin may be independent risk factors for osteoporotic fractures affecting different bone types and sites. Determining patient adipocytokine levels may help predict the occurrence of specific osteoporotic fractures, thereby enabling optimal treatment for osteoporosis and improving quality of life.
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Affiliation(s)
- Yukio Nakamura
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
| | - Masaki Nakano
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Takako Suzuki
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, 22 Sanban-cho, Chiyoda-ku, Tokyo 102-8341, Japan
| | - Junto Sato
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Hiroyuki Kato
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Jun Takahashi
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, 1610-1 Meisei, Misato, Azumino, Nagano 399-8101, Japan
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Vitamin K Nutrition and Bone Health. Nutrients 2020; 12:nu12071909. [PMID: 32605143 PMCID: PMC7399911 DOI: 10.3390/nu12071909] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/22/2020] [Accepted: 06/25/2020] [Indexed: 01/22/2023] Open
Abstract
Vitamin K is essential for blood coagulation and plays an important role in extrahepatic metabolism, such as in bone and blood vessels, and in energy metabolism. This review discusses the assessment of vitamin K sufficiency and the role of vitamin K in bone health. To elucidate the exact role of vitamin K in other organs, accurate tools for assessing vitamin K deficiency or insufficiency are crucial. Undercarboxylated vitamin K-dependent protein levels can be measured to evaluate tissue-specific vitamin K deficiency/insufficiency. Vitamin K has genomic action through steroid and xenobiotic receptor (SXR); however, the importance of this action requires further study. Recent studies have revealed that the bone-specific, vitamin K-dependent protein osteocalcin has a close relationship with energy metabolism through insulin sensitivity. Among the organs that produce vitamin K-dependent proteins, bone has attracted the most attention, as vitamin K deficiency has been consistently associated with bone fractures. Although vitamin K treatment addresses vitamin K deficiency and is believed to promote bone health, the corresponding findings on fracture risk reduction are conflicting. We also discuss the similarity of other vitamin supplementations on fracture risk. Future clinical studies are needed to further elucidate the effect of vitamin K on fracture risk.
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Kashiwabara S, Hosoe H, Ohno RI, Nagai R, Shiraki M. Development and Evaluation of Novel ELISA for Determination of Urinary Pentosidine. J Nutr Sci Vitaminol (Tokyo) 2020; 65:526-533. [PMID: 31902866 DOI: 10.3177/jnsv.65.526] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Pentosidine is the most well-characterized advanced glycation end product (AGE). It has been measured by HPLC, although this approach cannot be adapted to analyze many clinical samples and is also time-consuming. Furthermore, the detection of pentosidine using a reported ELISA kit and HPLC system requires pretreatment by heating, which generates artificial pentosidine leading to overestimation. We developed a novel pentosidine ELISA system that don't require sample pretreatment for analyzing urine samples. We then analyzed the accuracy, precision, and reliability of this system. Urinary samples for analysis were obtained from healthy volunteers and stored urinary samples from the participants of the Nagano cohort study were also used. The LoB and LoD were 4.25 and 6.24 pmol/mL, respectively. Intra- and inter-assay coefficients of variation were less than 5%. The spiking and dilution recoveries were 101.4% and 100.5%, respectively. Analysis of the cross-reactivities against seven compounds representative of AGEs and structurally similar to pentosidine showed no significant cross-reactivity. The correlation coefficient between the concentrations of pentosidine obtained from HPLC and ELISA for the same urine samples was r=0.815. The urinary excretion of pentosidine upon overnight fasting was lower than that after a meal, suggesting the presence of diurnal variation in urinary pentosidine. In contrast, day-to-day variation was not observed. These results indicate that the ELISA system has sufficient reliability, accuracy, and precision for measuring urinary pentosidine. Sampling of fasting urine is suitable for minimizing variation. In conclusion, this ELISA system is promising to evaluate the effect of AGE on lifestyle-related diseases.
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Affiliation(s)
| | | | - Rei-Ichi Ohno
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University
| | - Ryoji Nagai
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University
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Andrade VFC, Chula DC, Sabbag FP, Cavalheiro DDDS, Bavia L, Ambrósio AR, da Costa CRV, Dos Reis LM, Borba VZC, Moreira CA. Bone Histomorphometry in Young Patients With Type 2 Diabetes is Affected by Disease Control and Chronic Complications. J Clin Endocrinol Metab 2020; 105:5582037. [PMID: 31587051 DOI: 10.1210/clinem/dgz070] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/03/2019] [Indexed: 02/08/2023]
Abstract
CONTEXT Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures. No study has evaluated the correlation of bone histomorphometry (BH) parameters with glycemic control and presence of chronic complications (CCs) in premenopausal women with T2DM. OBJECTIVES To evaluate BH and correlate them with the degree of glycemic control and presence of CCs. DESIGN, SETTINGS, AND PATIENTS This was a cross-sectional study conducted at a tertiary medical center. Twenty-six premenopausal women with T2DM were divided into groups with glycated hemoglobin HbA1c < 7% (good control, GC; n = 10) and HbA1c > 7% (poor control, PC; n = 16), and further subdivided into groups with (n = 9) and without (n = 17) CCs. BH parameters (bone volume [bone volume per total volume, BV/TV], trabecular thickness [Tb.Th], trabecular number [Tb.N], trabecular separation [Tb.Sp], osteoid thickness [O.Th], osteoid surface [osteoid surface per bone surface, OS/BS]), mineralizing surface [MS/BS], bone formation rate [BFR]), mineral apposition rate [MAR]) as well as serum pentosidine (PEN) and insulin-like growth factor (IGF)-1 were measured. The BH data were compared among the groups and with a BH control group (control group, CG, n = 15) matched by age, sex, and race. RESULTS BV/TV was increased in GC (P < .001) and PC (P = .05) groups and O.th (P = .03) was smaller in the PC group than in the CG. A comparison of the groups with and without CCs with the CG showed in the group with CCs, O.Th was smaller(P = .01) and BV/TV similar to the CG (P = .11). HbA1c correlated negatively with O.Th (P = .02) and OS/BS (P = .01). There was no correlation of BH to PEN and IGF-1. CONCLUSION BH in premenopausal patients with T2DM is affected by disease control and chronic complications.
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Affiliation(s)
- Vicente F C Andrade
- Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Curitiba, Brazil
| | - Domingos C Chula
- Nephrology Unit, Clinics Hospital of Federal University of Parana, Curitiba, Brazil
| | - Fábio P Sabbag
- Ophthalmologist, retinal and vitreo specialist at the Clinic Center of Vision, Medical School of Ribeirão Preto, São Paulo University, Curitiba, São Paulo, Brazil
| | | | - Lorena Bavia
- Laboratory of Molecular Immunopathology, Department of Medical Pathology, Clinics Hospital of Federal do Parana University, Brazil
| | - Altair Rogério Ambrósio
- Laboratory of Molecular Immunopathology, Department of Medical Pathology, Clinics Hospital of Federal do Parana University, Brazil
| | | | - Luciene M Dos Reis
- LIM 16 - Laboratory of Renal Physiopathology, Clinics Hospital (HCFMUSP), School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Victória Z C Borba
- Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Curitiba, Brazil
| | - Carolina Aguiar Moreira
- Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Curitiba, Brazil
- Laboratory PRO, Section of bone histomorphometry, Fundação Pró-Renal, Curitiba, Brazil
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Kida Y, Saito M, Shinohara A, Soshi S, Marumo K. Non-invasive skin autofluorescence, blood and urine assays of the advanced glycation end product (AGE) pentosidine as an indirect indicator of AGE content in human bone. BMC Musculoskelet Disord 2019; 20:627. [PMID: 31881872 PMCID: PMC6933723 DOI: 10.1186/s12891-019-3011-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 12/17/2019] [Indexed: 12/21/2022] Open
Abstract
Background Bone mineral density (BMD) measurements are widely used to assess fracture risk. However, the finding that some fracture patients had high BMD together with the low contribution of drugs to osteoporosis suggests that bone strength factors other than BMD contribute to bone quality. We evaluated the amount of advanced glycation end products (AGEs) by non-invasive assays of serum and urine as well as by skin autofluorescence to measure the levels of a representative AGE, pentosidine, to investigate whether pentosidine can serve as an indirect indicator of AGEs formation in bone collagen. Methods A total of 100 spinal surgery patients without fragility fracture (54 males and 46 females) treated at our hospital were enrolled. The amount of pentosidine in blood, urine, skin and bone (lumbar lamina) samples from these patients was measured. AGE accumulation was assessed by measuring skin autofluorescence. We examined the correlation between pentosidine content in tissues and body fluid, as well as skin AGEs with age, height, body weight, BMI, and estimated glomerular filtration rate (eGFR). Results A significant age-related increase in pentosidine levels in tissues was observed, while there was a significant negative correlation between tissue pentosidine and eGFR. The amount of skin pentosidine was significantly and positively correlated with pentosidine content of the bone in those under 50 years of age. Urine pentosidine also correlated positively with bone pentosidine and skin pentosidine, but only in females. The total amount of AGEs in skin did not correlate with bone pentosidine. Conclusion In this study, the strong correlation between the pentosidine content in each sample and eGFR may indicate that renal dysfunction with advancing age increases oxidative stress and induces AGEs formation in collagen-containing tissues. The correlation of skin pentosidine concentration and eGFR, with AGEs formation in bone collagen suggests that pentosidine would be a useful indirect index of decreased bone quality. Skin AGEs estimated by autofluorescence in clinical situations may not be suitable as an indirect assessment of bone quality. Because urine pentosidine correlated positively with bone pentosidine and skin pentosidine in females, urine pentosidine may be a candidate for an indirect assessment of bone quality.
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Affiliation(s)
- Yoshikuni Kida
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
| | - Akira Shinohara
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Shigeru Soshi
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Keishi Marumo
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
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Shiraki M, Kashiwabara S, Imai T, Tanaka S, Saito M. The association of urinary pentosidine levels with the prevalence of osteoporotic fractures in postmenopausal women. J Bone Miner Metab 2019; 37:1067-1074. [PMID: 31214839 DOI: 10.1007/s00774-019-01017-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/03/2019] [Indexed: 12/13/2022]
Abstract
To evaluate whether or not the urinary pentosidine level has clinical value in the assessment of the osteoporotic fracture risk, a novel ELISA for pentosidine was used in clinical samples. This study employed a cross-sectional design to analyze a subset of postmenopausal women in the Nagano Cohort Study. A total of 517 urine samples were analyzed using an ELISA system, which can measure urinary pentosidine without hydrolysis. Patients were asked about their history of non-vertebral osteoporotic fracture and the prevalence of vertebral fracture was semi-quantitatively assessed on X-ray films. A 10-year increase in age was related to a 1.09-fold increase in the urinary pentosidine level (95% CI 1.05-1.13, P < 0.001), prevalent fracture (+) was related to a 1.10-fold increase in the urinary pentosidine level (95% CI 1.03-1.18, P = 0.006). Patients with prevalent fracture who had a normal bone mineral density (BMD) showed higher pentosidine levels (median 34.3 pM/mg Cr) than patients with a low BMD without fracture (median 31.4 pM/mg Cr). A multivariable logistic regression analysis revealed that urinary pentosidine was significantly associated with the prevalence of fracture after adjustment for known risk factors for fracture (odds ratio 1.92, 95% CI 1.09-3.37, P = 0.023). The present results indicated a significant association between urinary pentosidine and fracture after adjustment for age and BMD, suggesting that urinary pentosidine may be useful for assessing the fracture risk in postmenopausal women.
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Affiliation(s)
- Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, 1610-1, Meisei, Misato, Azumino, Nagano Prefecture, 399-8101, Japan.
| | | | - Takumi Imai
- Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shiro Tanaka
- Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Mitsuru Saito
- Department of Orthopedic Surger, Jikei University School of Medicine, Tokyo, Japan
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Executive summary of the Japan Osteoporosis Society Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition). Clin Chim Acta 2019; 498:101-107. [PMID: 31425674 DOI: 10.1016/j.cca.2019.08.012] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/14/2019] [Accepted: 08/14/2019] [Indexed: 12/17/2022]
Abstract
With the aging of society, the number of osteoporosis-related fractures is increasing. Prevention of osteoporosis and maintenance of the quality of life of osteoporosis patients require early diagnosis, effective treatment, and highly precise treatment monitoring. Although bone biopsy is clinically one of the essential techniques for diagnosis of osteoporosis, it is invasive and difficult to perform in general clinical practice. Bone mineral density measurement is another essential technique available in clinical practice that provides good precision. However, it is not effective for determining the appropriate treatment options or evaluating short-term treatment efficacy. On the other hand, bone turnover markers (BTMs) have gained attention because they provide information that is valuable for both the selection of treatment and short-term monitoring. BTMs are now positioned to become a tool for clinically assessing bone turnover outcomes. Since the Japan Osteoporosis Society issued its Guidelines for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis in 2012, new drugs, drug formulations, and combination drug therapies have been approved; therefore, we updated the 2012 guidelines in the Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).
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Kimura T, Koike Y, Aikawa K, Kimura S, Mori K, Sasaki H, Miki K, Watanabe K, Saito M, Egawa S. Short-term impact of androgen deprivation therapy on bone strength in castration-sensitive prostate cancer. Int J Urol 2019; 26:980-984. [PMID: 31353680 DOI: 10.1111/iju.14077] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/01/2019] [Indexed: 01/05/2023]
Abstract
OBJECTIVES To prospectively evaluate changes in bone quality and bone mineral density after androgen deprivation therapy in castration-sensitive prostate cancer. METHODS A total of 32 patients with castration-sensitive prostate cancer who were scheduled for androgen deprivation therapy for >12 months were included. The bone mineral density of the femoral neck and lumbar spine was evaluated before, and 6 and 12 months after androgen deprivation therapy. Bone metabolic (serum undercarboxylated osteocalcin, tartrate-resistant acid phosphatase 5b and procollagen type I propeptides) and bone quality markers (plasma pentosidine and homocysteine) were measured before, and 3, 6 and 12 months after androgen deprivation therapy. RESULTS The median patient age was 71 years. A total of 17 patients were treated primarily with androgen deprivation therapy, and 15 were treated with androgen deprivation therapy in combination with definitive radiotherapy. Bone quality markers did not change substantially after androgen deprivation therapy. Bone mineral density decreased significantly after 12 months of androgen deprivation therapy. Serum undercarboxylated osteocalcin and tartrate-resistant acid phosphatase 5b levels increased significantly 3 months after androgen deprivation therapy, but procollagen type I propeptides levels stayed unchanged. CONCLUSIONS Bone quality markers do not change substantially after androgen deprivation therapy, whereas bone mineral density decreases significantly. Bone turnover markers might play an important role in monitoring bone health during androgen deprivation therapy.
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Affiliation(s)
- Takahiro Kimura
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Koike
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Koichi Aikawa
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Shoji Kimura
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Keiichiro Mori
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Hiroshi Sasaki
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Kenta Miki
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Ken Watanabe
- Department of Radiology, Jikei University School of Medicine, Tokyo, Japan
| | - Mitsuru Saito
- Department of Orthopedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Shin Egawa
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
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Asadipooya K, Uy EM. Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature. J Endocr Soc 2019; 3:1799-1818. [PMID: 31528827 PMCID: PMC6734192 DOI: 10.1210/js.2019-00160] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 07/03/2019] [Indexed: 12/24/2022] Open
Abstract
Diabetes compromises bone cell metabolism and function, resulting in increased risk of fragility fracture. Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) and can make a meaningful contribution to bone cell metabolism and/or alter function. Searches in PubMed using the key words "advanced glycation end-product," "RAGE," "sRAGE," "bone," and "diabetes" were made to explain some of the clinical outcomes of diabetes in bone metabolism through the AGE-RAGE signaling pathway. All published clinical studies were included in tables. The AGE-RAGE signaling pathway participates in diabetic complications, including diabetic osteopathy. Some clinical results in diabetic patients, such as reduced bone density, suppressed bone turnover markers, and bone quality impairment, could be potentially due to AGE-RAGE signaling consequences. However, the AGE-RAGE signaling pathway has some helpful roles in the bone, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either conditions of RAGE production or destruction, and then it cannot always reflect the AGE-RAGE signaling. Recombinant sRAGE can block the AGE-RAGE signaling pathway but is associated with some limitations, such as accessibility to AGEs, an increase in other RAGE ligands, and a long half-life (24 hours), which is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.
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Affiliation(s)
- Kamyar Asadipooya
- Division of Endocrinology and Molecular Medicine, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Edilfavia Mae Uy
- Division of Endocrinology and Molecular Medicine, Department of Medicine, University of Kentucky, Lexington, Kentucky
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Kanazawa M, Matsumoto Y, Takahashi K, Suzuki H, Uzuka H, Nishimiya K, Shimokawa H. Treadmill exercise prevents reduction of bone mineral density after myocardial infarction in apolipoprotein E-deficient mice. Eur J Prev Cardiol 2019; 27:28-35. [PMID: 30857427 DOI: 10.1177/2047487319834399] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIMS Recent clinical studies demonstrated the association between myocardial infarction (MI) and osteoporotic fractures. We examined whether MI causes bone loss and the effects of exercise training on bone in mice after MI. METHODS We created a MI model in 16-week-old male apolipoprotein E-deficient mice (n = 42), which were randomly assigned to exercise group (MI-Ex) and sedentary group (MI-Sed). We also performed sham operations in other mice (n = 10). Treadmill exercise training was performed from one week after operation to eight weeks. At eight weeks, the bone parameters of the femur were measured by quantitative computed tomography, followed by histological analysis (n = 10-17). RESULTS Bone mineral density (BMD) of the femur was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.001), whereas the BMD was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In histological analysis, Rho-associated coiled-coil kinase 2 and tartrate-resistant acid phosphate positive (bone resorptive) area in distal femur were significantly increased in the MI-Sed group as compared with the sham group (P < 0.05), whereas those parameters were significantly decreased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In contrast, alkaline phosphatase (ALP)-positive (bone-forming) area was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.05), whereas ALP-positive area was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). CONCLUSIONS The present study demonstrates that MI reduces BMD and treadmill exercise training prevents the reduction of BMD in apolipoprotein E-deficient mice.
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Affiliation(s)
- Masanori Kanazawa
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuharu Matsumoto
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kikuyo Takahashi
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideaki Suzuki
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hironori Uzuka
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kensuke Nishimiya
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroaki Shimokawa
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Choi DH, Lee SM, Lim SA, Choi YS. Feasibility of Serum Pentosidine Level as a Potential Risk Factor for Osteoporotic Vertebral Compression Fracture. Asian Spine J 2018; 12:992-997. [PMID: 30322258 PMCID: PMC6284123 DOI: 10.31616/asj.2018.12.6.992] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 05/08/2018] [Indexed: 01/22/2023] Open
Abstract
Study Design Feasibility study. Purpose To evaluate the feasibility of using serum pentosidine level as a potential marker for osteoporotic vertebral compression fracture (OVCF). Overview of Literature A review of previous studies suggests a negative correlation between serum pentosidine concentration and bone strength. However, it is unclear whether serum pentosidine level might be a potential marker of OVCF in Koreans. Methods Forty patients who underwent bone mineral density examination were included in this study, and their serum pentosidine levels were prospectively analyzed. Serum pentosidine level was evaluated using enzyme-linked immunosorbent assay. Among all the patients, 11 with OVCF were assigned to the vertebral fracture group and 29 who did not have vertebral fracture were included in the non-fracture group. In addition, we used the Fracture Risk Assessment (FRAX) tool Korean version for assessing the 10-year probability of fracture. Results There was a statistically significant difference in the mean serum pentosidine level (p=0.04) of the vertebral fracture group (110.8 ng/mL) and the non-fracture group (64.3 ng/mL). Logistic regression analyses showed that serum pentosidine was significantly associated with OVCF. The vertebral fracture group had significantly higher 10-year probability of major osteoporotic fracture as per FRAX than the non-fracture group. There was a positive correlation between pentosidine level and FRAX results (r=0.35, p=0.02). Conclusions These results suggest that increased serum pentosidine level could be a potential marker for OVCF.
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Affiliation(s)
- Dong-Hyuk Choi
- Department of Orthopaedic Surgery, Kwangju Christian Hospital, Gwangju, Korea
| | - Sang-Min Lee
- Department of Orthopaedic Surgery, Kwangju Christian Hospital, Gwangju, Korea
| | - Sung-An Lim
- Department of Orthopaedic Surgery, Kwangju Christian Hospital, Gwangju, Korea
| | - Yong-Soo Choi
- Department of Orthopaedic Surgery, Kwangju Christian Hospital, Gwangju, Korea
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Identification of Antiglycative Compounds in Japanese Red Water Pepper (Red Leaf Variant of the Persicaria hydropiper Sprout). Molecules 2018; 23:molecules23092319. [PMID: 30208642 PMCID: PMC6225476 DOI: 10.3390/molecules23092319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/10/2018] [Accepted: 09/10/2018] [Indexed: 01/14/2023] Open
Abstract
Glycation, the nonenzymatic reaction between proteins and excess blood sugar, is implicated in multiple disorders and occurs via the formation and accumulation of advanced glycation end products (AGEs). In our previous studies, we demonstrated that the red-leaf variant of the Persicaria hydropiper sprout (Japanese red water pepper, Benitade) is one of the potent plants that inhibit formation of AGEs. In this study, we aimed to identify antiglycative compounds in Benitade. Benitade extracts were prepared with hot water, then fractionated by using high-performance liquid chromatography (HPLC). The antiglycative efficacy of each fraction was evaluated by measuring the formation of fluorescent AGEs (Ex 370 nm/Em 440 nm). Two fractions, which contained peaks at 26.4 min and 31.8 min, showed potent antiglycative efficacy. When we hydrolyzed these peaks, they shifted to 32.5 and 41.4 min, which are the same retention times as cyanidin and quercetin, respectively. Based on thin-layer chromatography, both compounds contained galactose. Finally, ultrahigh-performance liquid chromatography/quadrupole-time of flight mass spectrometry (UHPLC-QqTOF-MS) analyses were performed to determine the structure of those compounds. Overall, we identified two glycosides, cyanidin 3-O-galactoside (idaein) and quercetin 3-O-galactoside (hyperin), as representative antiglycative compounds in Benitade.
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