Reduced concentrations of collagen cross-links are associated with reduced strength of bone

wbldb

Oxlund, H.¹; Barckman, M.¹; Ørtoft, G.¹; Andreassen, T. T.¹

Reduced concentrations of collagen cross-links are associated with reduced strength of bone

Bone. October 1995;17(4)(suppl):S365-S371

Affiliations

¹Dept. of Connective Tissue Biology, Institute of Anatomy, University of Aarhus, 8000 Aarhus C, USA
Abstract

The known cross-links of bone collagen are derived from lysine and hydroxylysine. The first step in the enzymatic cross-linking process is a deamination by lysyl oxidase producing an aldehyde which then may condense with a lysyl or hydroxylysyl residue of a neighbouring collagen molecule. Some of the resulting divalent aldimine and oxo-imine cross-links may later on be incorporated in trivalent hydroxylysyl-pyridinoline and lysyl-pyridinoline cross-links. In bone collagen prepared from the cancellous bone of vertebral bodies of osteoporotic individuals we found a reduced stability towards acetic acid and pepsin, and a substantial reduction in the concentration of the divalent collagen cross-links compared with sex- and age-matched controls. To what extent do the collagen cross-links influence the mechanical properties of bone? β-amino-propionitrile (BAPN) irreversibly inhibits the enzyme lysyl oxidase and therefore, the formation of cross-links between the collagen molecules. In the present study female rats, 70 days old, injected subcutaneously two times daily with BAPN (333 mg/kg/day) for 1 month and saline injected control rats were studied. The concentration of the hydroxypyridinium cross-links of femoral mid-diaphyseal cortical bone was determined by HPLC with fluorescence detection and the mechanical properties of the rat femoral diaphyses were analyzed by a materials testing machine. The BAPN injections resulted in a 45% reduction in the concentration of the hydroxypyridinium crosslinks and a 31% decrease in the stability of the bone collagen towards acetic acid and pepsin compared with the control rats. No changes were found in ash or collagen concentrations of the cortical bone. The mid-diaphyseal deflection until breaking, bending stress and elastic stiffness (Young's modulus) of the BAPN injected rats were decreased by 21%, 26% and 30%, respectively, compared with the control rats. The present study shows that collagen cross-links are essential for bone to possess a sufficient deflection capacity, bending strength and stiffness.
Links

DOI: 10.1016/8756-3282(95)00328-B

PubMed: 8579939

WoS: A1995TE57600034

Cited Works (6)

Year	Entry
1987	Parfitt AM. Bone remodeling and bone loss: understanding the pathophysiology of osteoporosis. Clin Obstet Gynecol. December 1987;30(4):789-811.
1993	Ejersted C, Andreassen TT, Oxlund H, Jørgensen PH, Bak B, Häggblad J, Tørring O, Nilsson MHL. Human parathyroid hormone (1–34) and (1–84) increase the mechanical strength and thickness of cortical bone in rats. J Bone Miner Res. September 1993;8(9):1097-1101.
1993	Bailey AJ, Wotton SF, Sims TJ, Thompson PW. Biochemical changes in the collagen of human osteoporotic bone matrix. Connect Tissue Res. 1993;29(2):119-132.
1988	Eyre DR, Dickson IR, Van Ness K. Collagen cross-linking in human bone and articular cartilage: age-related changes in the content of mature hydroxypyridinium residues. Biochem J. June 1988;252(2):495-500.
1986	Mosekilde L, Mosekilde L. Normal vertebral body size and compressive strength: relations to age and to vertebral and iliac trabecular bone compressive strength. Bone. 1986;7(3):207-212.
1985	Frost HM. The pathomechanics of osteoporoses. Clin Orthop Relat Res. November 1985;200:198-225.

Cited By (70)

Year	Entry
2004	Wang X, Puram S. The toughness of cortical bone and its relationship with age. Ann Biomed Eng. January 2004;32(1):123-135.
1998	Bank RA, Bayliss MT, Lafeber FPJG, Maroudas A, Tekoppele JM. Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage: the age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. Biochem J. February 15, 1998;3301(1):345-351.
2008	Matsuura M, Eckstein F, Lochmüller E-M, Zysset PK. The role of fabric in the quasi-static compressive mechanical properties of human trabecular bone from various anatomical locations. Biomech Model Mechanobiol. February 2008;7(1):27-42.
1996	Oxlund H, Mosekilde L, Ørtoft G. Reduced concentration of collagen reducible cross links in human trabecular bone with respect to age and osteoporosis. Bone. November 1996;19(5):479-484.
1998	Knott L, Bailey AJ. Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone. March 1998;22(3):181-187.
2001	Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. February 2001;28(2):195-201.
2005	Hernandez CJ, Tang SY, Baumbach BM, Hwu PB, Sakkee AN, van der Ham F, DeGroot J, Bank RA, Keaveny TM. Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen cross-links. Bone. December 2005;37(6):825-832.
2006	Nyman JS, Roy A, Acuna RL, Gayle HJ, Reyes MJ, Tyler JH, Dean DD, Wang X. Age-related effect on the concentration of collagen crosslinks in human osteonal and interstitial bone tissue. Bone. December 2006;39(6):1210-1217.
2007	Wallace JM, Rajachar RM, Allen MR, Bloomfield SA, Robey PG, Young MF, Kohn DH. Exercise-induced changes in the cortical bone of growing mice are bone- and gender-specific. Bone. April 2007;40(4):1120-1127.
2010	Bala Y, Farlay D, Delmas PD, Meunier PJ, Boivin G. Time sequence of secondary mineralization and microhardness in cortical and cancellous bone from ewes. Bone. April 2010;46(4):1204-1212.
2011	Paschalis EP, Tatakis DN, Robins S, Fratzl P, Manjubala I, Zoehrer R, Gamsjaeger S, Buchinger B, Roschger A, Phipps R, Boskey AL, Dall'Ara E, Varga P, Zysset P, Klaushofer K, Roschger P. Lathyrism-induced alterations in collagen cross-links influence the mechanical properties of bone material without affecting the mineral. Bone. December 2011;49(6):1232-1241.
2013	Willett TL, Sutty S, Gaspar A, Avery N, Grynpas M. In vitro non-enzymatic ribation reduces post-yield strain accommodation in cortical bone. Bone. February 2013;52(2):611-622.
2007	Allen MR, Burr DB. Mineralization, microdamage, and matrix: how bisphosphonates influence material properties of bone. BoneKEy Osteovision. February 2007;4(2):49-60.
2002	Wang X, Li X, Bank RA, Agrawal CM. Effects of collagen unwinding and cleavage on the mechanical integrity of the collagen network in bone. Calcif Tiss Int. August 2002;71(2):186-192.
2006	Saito M, Fujii K, Marumo K. Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tiss Int. September 2006;79(3):160-168.
2000	Wang X, Bank RA, TeKoppele JM, Hubbard GB, Althanasiou KA, Agrawal CM. Effect of collagen denaturation on the toughness of bone. Clin Orthop Relat Res. February 2000;371:228-239.
2020	Whyne CM, Ferguson D, Clement A, Rangrez M, Hardisty M. Biomechanical properties of metastatically involved osteolytic bone. Curr Osteoporos Rep. December 2020;18(6):705-715.
2008	Siegmund T, Allen MR, Burr DB. Failure of mineralized collagen fibrils: modeling the role of collagen cross-linking. J Biomech. 2008;41(7):1427-1435.
2011	Willems NMBK, Mulder L, Bank RA, Grünheid T, Toonder JMJd, Zentner A, Langenbach GEJ. Determination of the relationship between collagen cross-links and the bone–tissue stiffness in the porcine mandibular condyle. J Biomech. April 7, 2011;44(6):1132-1136.
2021	Unal M. Raman spectroscopic determination of bone matrix quantity and quality augments prediction of human cortical bone mechanical properties. J Biomech. April 15, 2021;119:110342.
1999	Zioupos P, Currey JD, Hamer AJ. The role of collagen in the declining mechanical properties of aging human cortical bone. J Biomed Mater Res. May 1999;A45(2):108-116.
2002	Banse X, Sims TJ, Bailey AJ. Mechanical properties of adult vertebral cancellous bone: correlation with collagen intermolecular cross-links. J Bone Miner Res. July 2002;17(9):1621-1628.
2003	Paschalis EP, Boskey AL, Kassem M, Eriksen EF. Effect of hormone replacement therapy on bone quality in early postmenopausal women. J Bone Miner Res. June 2003;18(6):955-959.
2003	Paschalis E, Recker R, Dicarlo E, Doty S, Atti E, Boskey A. Distribution of collagen cross-links in normal human trabecular bone. J Bone Miner Res. November 2003;18(11):1942-1946.
2006	Durchschlag E, Paschalis EP, Zoehrer R, Roschger P, Fratzl P, Recker R, Phipps R, Klaushofer K. Bone material properties in trabecular bone from human iliac crest biopsies after 3‐ and 5‐year treatment with risedronate. J Bone Miner Res. October 2006;21(10):1581-1590.
2015	McNerny EMB, Gong B, Morris MD, Kohn DH. Bone fracture toughness and strength correlate with collagen cross-link maturity in a dose-controlled lathyrism mouse model. J Bone Miner Res. March 2015;30(3):455-464.
2016	Paschalis EP, Gamsjaeger S, Fratzl-Zelman N, Roschger P, Masic A, Brozek W, Hassler N, Glorieux FH, Rauch F, Klaushofer K, Fratzl P. Evidence for a role for nanoporosity and pyridinoline content in human mild osteogenesis imperfecta. J Bone Miner Res. May 2016;31(5):1050-1059.
2021	Hunt HB, Miller NA, Hemmerling KJ, Koga M, Lopez KA, Taylor EA, Sellmeyer DE, Moseley KF, Donnelly E. Bone tissue composition in postmenopausal women varies with glycemic control from normal glucose tolerance to type 2 diabetes mellitus. J Bone Miner Res. February 2021;36(2):334-346.
1997	Bank RA, Beekman B, Verzijl N, de Roos JADM, Nico Sakkee A, TeKoppele JM. Sensitive fluorimetric quantitation of pyridinium and pentosidine crosslinks in biological samples in a single high-performance liquid chromatographic run. J Chromatogr B Biomed Sci Appl. December 5, 1997;703:37.
2004	Fratzl P, Gupta HS, Paschalis EP, Roschger P. Structure and mechanical quality of the collagen–mineral nano-composite in bone. J Mater Chem. 2004;14(14):2115-2123.
2001	Wang X, Bank RA, Tekoppele JM, Agrawal CM. The role of collagen in determining bone mechanical properties. J Orthop Res. 2001;19(6):1021-1026.
2005	Nyman JS, Reyes M, Wang X. Effect of ultrastructural changes on the toughness of bone. Micron. October–December 2005;36(7-8):566-582.
2001	Thompson JB, Kindt JH, Drake B, Hansma HG, Morse DE, Hansma PK. Bone indentation recovery time correlates with bond reforming time. Nature. December 13, 2001;414(6865):773-776.
2006	Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. March 2006;17(3):319-336.
2006	Saito M, Fujii K, Soshi S, Tanaka T. Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int. July 2006;17(7):986-995.
2008	Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD. Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int. March 2008;19(3):329-337.
2008	Ruppel ME, Miller LM, Burr DB. The effect of the microscopic and nanoscale structure on bone fragility. Osteoporos Int. September 2008;19(9):1251-1265.
2008	Saito M, Mori S, Mashiba T, Komatsubara S, Marumo K. Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. Osteoporos Int. September 2008;19(9):1343-1354.
2010	Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21(2):195-214.
2014	Fonseca H, Moreira-Gonçalves D, Coriolano H-JA, Duarte JA. Bone quality: the determinants of bone strength and fragility. Sports Med. January 2014;44(1):37-53.
2017	Unal M. Classification of Bound Water and Collagen Denaturation Status of Cortical Bone by Raman Spectroscopy [PhD thesis]. Cleveland, OH: Case Western Reserve University; January 2017.
2017	Heveran CM. Bone Tissue Material Properties Are Altered in Chronic Kidney Disease to Lower Fracture Resistance Determining Bone Quality [PhD thesis]. University of Colorado; 2017.
2022	Senwar B. Bone Material Quality, Structure, and Functional Relationships Contribute to Bone Strength and Toughness [Master's thesis]. University of Colorado; 2022.
2013	Kim G. The Effects of Mineralization and Crystallinity on the Mechanical Behavior of Bone [PhD thesis]. Ithaca, NY: Cornell University; May 2013.
2018	Hunt HB. Characterization of Material Properties, Microarchitecture, and Mechanics of Bone from Subjects With Type 2 Diabetes Mellitus [PhD thesis]. Ithaca, NY: Cornell University; December 2018.
2002	Hengsberger S. Mechanical Characterization of Bone from the Tissue Down to the Lamellar Level by Means of Nanoindentation [PhD thesis]. Lausanne, Switzerland: École Polytechnique Fédérale de Lausanne; 2002.
2022	Peruzzi CRP. Nanoscale Deformation Mechanisms and Yield Prediction of Lamellar Bone [PhD thesis]. Swiss Federal Institute of Technology Zürich; 2022.
2015	Newman CL. Assessing and Modifying Bone Quality in Chronic Kidney Disease [PhD thesis]. Indianapolis, IN: Indiana University; May 2015.
2008	Courtland H-W. Intra-Species Variation in Skeletal Mechanical Function is Achieved Through Genetic Regulation of Both the Quality and Morphology of Bone [PhD thesis]. Mount Sinai School of Medicine; 2008.
2017	Kreipke TC. Structural, Mechanical, and Biological Relationships of Trabecular Bone in Osteoporosis [PhD thesis]. University of Notre Dame; April 2017.
2009	Lievers WB. Effects of Geometric and Material Property Changes on the Apparent Elastic Properties of Cancellous Bone [PhD thesis]. Queen's University; April 2009.
2009	Ruppel ME. Alterations in the Mineral and Collagen Matrix of Bisphosphonate-Treated Bone and Osteoblasts [PhD thesis]. Stony Brook, NY: Stony Brook University; May 2009.
2004	LaMothe JM. Functional Adaptation of Bone [PhD thesis]. Calgary, AB: University of Calgary; September 2004.
2016	Pangka AVS. Biomechanical Measures of the Muscle-Bone Unit in Postmenopausal Females: A Pilot Study [Master's thesis]. Calgary, AB: University of Calgary; August 2016.
2014	Nawathe S. Micromechanics of the Human Proximal Femur: Role of Microstructure and Tissue-Level Ductility on Femoral Strength [PhD thesis]. Berkeley, CA: Berkeley, University of California; 2014.
1998	Ahsan T. Integrative Repair and Collagen Crosslinking in Articular Cartilage [PhD thesis]. San Diego (UCSD), University of California; 1998.
2005	Kozloff KM. Influence of a Collagen Mutation of the Mechanical Nature of Bone: Governing Factors in a Disease Model for Osteogenesis Imperfecta Type IV [PhD thesis]. University of Michigan; 2005.
2007	Wallace JM III. Investigating the Inbred Strain-Specific Response to Biglycan-Deficiency and Exercise: A Study in Genetically-Mediated Skeletal Adaptation [PhD thesis]. University of Michigan; 2007.
2014	McNerny EMB. Collagen Cross-Linking as a Determinant of Bone Quality: The Importance of Cross-Linking to Mechanical Properties as Explored by Cross-Link Inhibition and Exercise [PhD thesis]. University of Michigan; 2014.
2019	Surowiec R. Novel Models to Image and Quantify Bone Drug Efficacy and Disease Progression in Vivo: Addressing the Fragility Phenotype [PhD thesis]. University of Michigan; 2019.
2016	Vrahna C. Investigating the Effects of Downstream Parathyroid Hormone (PTH) Targets on Bone Strength and Quality [PhD thesis]. Melbourne, Australia: The University of Melbourne; December 2016.
2022	Snow TJ. An Investigation of the Role of Collagen Network on the Dynamic Fracture Initiation Toughness of Bovine Cortical Bone [Master's thesis]. University of Utah; December 2022.
2010	Kyle KA. Differential Effects of PPAR-Γ Activation Vs. Chemical or Genetic Reduction of DPP-4 Activity on Murine Bone Quality [Master's thesis]. University of Toronto; 2010.
2010	Wynnyckyj C. The Consequences of Collagen Degradation on Bone Mechanical Properties [PhD thesis]. University of Toronto; 2010.
2018	Burke MV. Quantification of Changes in Vertebral Bone Quality in the Presence of Metastases [PhD thesis]. University of Toronto; 2018.
2010	Banka M. Microdamage Induced Collagen Denaturation in Bone [Master's thesis]. San Antionio, TX: University of Texas at San Antonio; December 2010.
2010	Reyes MJ. Age-Related Influence of Bone Remodeling on Local Tissue Properties of Human Cortical Bone [PhD thesis]. San Antionio, TX: University of Texas at San Antonio; December 2010.
2011	Islam A. Mechanistic Model of Nanoscratch Test to Determine the in Situ Toughness of Bone [Master's thesis]. San Antionio, TX: University of Texas at San Antonio; May 2011.
2022	Martel DR. Contributors to Proximal Femur Fracture Force: Multiscale Considerations of Rate, Toughness, and Bone Composition [PhD thesis]. University of Waterloo; 2022.
2011	Horch RA. Studies of ¹H Nuclear Magnetic Resonance Relaxation in Human Cortical Bone: From Ex Vivo Spectroscopy to Clinical Imaging Methods [PhD thesis]. Nashville, TN: Vanderbilt University; December 2011.