The Role of Metabolomics in Osteoarthritis Research

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The Role of Metabolomics in Osteoarthritis Research
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  The Role of Metabolomics inOsteoarthritis Research Metabolomics is the comprehensiveanalysis of small molecules in a bio-logic system. It has generated greatinterest by identifying novel bio-markers for disease diagnosis andpharmaceutical treatment, such ascitrate and choline as biomarkersfor prostate and breast cancer, re-spectively. Both tests are now clini-cally available and supported bymost health insurance providers. 1,2 Metabolitesaretheendproductsof cellularprocesses,andtheirlevelscanbe regarded as the ultimate responseofbiologicsystemstogenotype,phe-notype, and environmental condi-tions. They encompass a diversegroupoflow-molecular-weightcom-pounds,includinglipids,aminoacids,peptides,nucleicacids,organicacids,vitamins, thiols, and carbohy-drates, 3 and are commonly analyzedusing nuclear magnetic resonancespectroscopy,liquidchromatography/ mass spectrometry, and/or gaschromatography/mass spectrometry.Metabolomics may be well suitedfor research into osteoarthritis(OA) for such reasons as the greatheterogeneity in the disease processand recognition that no single bio-marker can reflect the breadth of temporal and pathologic processesassociated with OA. 4 Combiningseveral biomarkers into a panellikely will increase the discrimina-tory capability, 5 as would occurwith metabolic profiling. In addi-tion, because metabolic perturba-tions occur in real time, they indi-cate the current disease state, whichis a distinct advantage over currentclinical diagnostics and disease-monitoring techniques for OA,such as radiography.Metabolomics has been employedto detect metabolic perturbations inthe urine, blood, synovium, and sy-novial fluid (SF) of animal modelsand patients with OA. Lamers et al 6 used nuclear magnetic resonance tostudy the urine from Dunkin Hart-ley guinea pigs that spontaneouslydevelop OA. Disturbances in lacticacid, malic acid, hypoxanthine, andalanine were found to contributeheavily to the metabolic profile of OA. These investigators furtherstudied the urine of humans withand without OA and found distinctpatterns in the nuclear magneticresonance spectra that discrimi-nated between groups. 4 Zhai et al 7 employed metabolomics on humanserum in a study of patients withand without knee OA. These inves-tigators demonstrated that the ra-tios of valine and leucine to histi-dine were predictive of OA, therebypointing toward interest in the useof branched-chain amino acids aspotential biomarkers. 7 Many of these studies of venous plasma orurine identify metabolites that maybe related to aging, altered musclemass, and other factors that mayconfound the unique signature of apathologic OA joint. For these rea-sons, SF may yield the most accu-rate, real-time, and joint-specificmetabolic profile.Damyanovichetal 8 performedme-tabolomics on SF from experimen-tally induced OA in canine kneejoints. The nuclear magnetic reso-nancespectrademonstratedincreasedconcentrations of lactate, pyruvate,glycerol,alanine,isoleucine,hydroxy-butyrate, hydroxyisobutyrate, andlipoprotein-associated fatty acids.These investigators concluded thattheintra-articularenvironmentofOA Samuel B. Adams, Jr, MDLori A. Setton, PhDDana L. Nettles, PhD Topics from the frontiers of basicresearch presented by theOrthopaedic Research Society.From the Department ofOrthopaedic Surgery, DukeUniversity Medical Center(Dr. Adams), and the Department ofBiomedical Engineering, DukeUniversity (Dr. Setton andDr. Nettles), Durham, NC.Dr. Setton or an immediate familymember has received royalties fromStryker Orthopaedics and CytexTherapeutics; is a member of aspeakers’ bureau or has made paidpresentations on behalf of, is anemployee of, serves as a paidconsultant to, and has stock or stockoptions held in Cytex Therapeutics;and serves as a board member,owner, officer, or committee memberof the Orthopaedic ResearchSociety and the BiomedicalEngineering Society. Neither of thefollowing authors nor any immediatefamily member has receivedanything of value from or has stockor stock options held in acommercial company or institutionrelated directly or indirectly to thesubject of this article: Dr. Adams andDr. Nettles. J Am Acad Orthop Surg   2013;21:63-64http://dx.doi.org/10.5435/ JAAOS-21-01-63Copyright 2013 by the AmericanAcademy of Orthopaedic Surgeons. On the Horizon From the ORS January 2013, Vol 21, No 1  63  wasmorehypoxicandacidoticthaninthe normal joint and that arthriticjoints may rely in part on altered lipidmetabolic pathways.Wehaveperformedmetabolomicsonboth human synovium and SF. In ourfirststudy,themetabolicprofileofcon-ditioned media collected from syno-viumexplantcultureswasobtainedfortissues from patients undergoing totalknee arthroplasty (end-stage OA) andfrom patients undergoing ligament ormeniscal repair with little or no evi-dence of OA. 9 Thirteen metaboliteswere significantly elevated in theend-stage OA group, including gluta-mine, succinate, and pro-hydroxy-proline. Despite results suggestive of a distinct metabolic profile in OA,the synovium culture method doesnot easily translate into clinical prac-tice.In a second study, we performedmetabolomics on ankle SF of pa-tients with and without ankle OA. 10 Results identified 106 metabolites assignificantly elevated in the OA sam-ples and represented perturbations invirtually all metabolic pathways, in-cluding amino acid metabolism, car-bohydrate metabolism, mitochon-drial oxidation, lipid metabolism,peptide, vitamin, nucleotide synthe-sis, and oxidation-reduction homeo-stasis. More importantly, when a rig-orous decision tree analysis wasapplied to the metabolic profiles of the two populations, a 90% discrim-inatory accuracy was achieved, indi-cating the potential use of this tech-nology as a diagnostic tool for OA.Studies are ongoing to confirm thesefindings in a larger population andto generate a narrowed panel of met-abolic biomarkers and measurementmethods for translation into theclinic.Metabolic profiling of biofluidsand tissues can provide a panoramicview of the current physiologic stateof a biologic system, such as theintra-articular environment of an os-teoarthritic joint. We envision therole of metabolomics for OA as aclinically applied diagnostic tool inwhich a sample of a patient’s SFwould be analyzed for a panel of me-tabolite biomarkers, similar to fol-lowing the serial values from a com-plete blood count. Alterations in themetabolic profile could indicate dis-ease progression or a therapeutic re-sponse at a resolution not possiblewith currently employed clinicaltechniques. References 1. Serkova NJ, Spratlin JL, Eckhardt SG:NMR-based metabolomics:Translational application and treatmentof cancer.  Curr Opin Mol Ther  2007;9(6):572-585.2. Bartella L, Thakur SB, Morris EA, et al:Enhancing nonmass lesions in the breast:Evaluation with proton (1H) MRspectroscopy.  Radiology  2007;245(1):80-87.3. Zhang A, Sun H, Wang P, Han Y, WangX: Recent and potential developments of biofluid analyses in metabolomics.  J Proteomics  2012;75(4):1079-1088.4. Lamers RJ, van Nesselrooij JH, KrausVB, et al: Identification of an urinarymetabolite profile associated withosteoarthritis.  Osteoarthritis Cartilage 2005;13(9):762-768.5. Garnero P, Rousseau JC, Delmas PD:Molecular basis and clinical use of biochemical markers of bone, cartilage,and synovium in joint diseases.  ArthritisRheum  2000;43(5):953-968.6. Lamers RJ, DeGroot J, Spies-Faber EJ,et al: Identification of disease- andnutrient-related metabolic fingerprints inosteoarthritic Guinea pigs.  J Nutr  2003;133(6):1776-1780.7. Zhai G, Wang-Sattler R, Hart DJ, et al:Serum branched-chain amino acid tohistidine ratio: A novel metabolomicbiomarker of knee osteoarthritis.  AnnRheum Dis  2010;69(6):1227-1231.8. Damyanovich AZ, Staples JR, Chan AD,Marshall KW: Comparative study of normal and osteoarthritic caninesynovial fluid using 500 MHz 1Hmagnetic resonance spectroscopy.  J Orthop Res  1999;17(2):223-231.9. Adams SB Jr, Setton LA, Kensicki E, Bo-lognesi MP, Toth AP, Nettles DL: Globalmetabolic profiling of humanosteoarthritic synovium.  OsteoarthritisCartilage  2012;20(1):64-67.10. Adams SB Jr, Jones LC, Haile A, MillerSD, Gutyon GP, Schon LC:Inflammatory cytokine composition andmetabolic profile of post-traumatic anklejoint arthritis.  Transactions of theOrthopaedic Research Society  [CD-ROM] 2012;37:Poster 1788. On the Horizon From the ORS 64  Journal of the American Academy of Orthopaedic Surgeons
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