Biomarkers of osteoarthritis: translating information from in vitro culture systems to human patients

摘要

Biomarkers are anatomic, physiologic, biochemical, ormolecular parameters that may be associated with thepresence and severity of a specific disease. They aredetectable by using a variety of methods, including physicalexamination, laboratory assays, and imaging andcan be used as indicators of pharmacologic responses totherapeutic interventions. Despite the interest in biomarkers,there are currently no reliable, quantifiable andeasily measured markers that provide an earlier diagnosisof arthritic diseases such as osteoarthritis (OA), especiallyduring the asymptomatic and pre-radiographic stages ofthe disease. For example, many of the existing biomarkersof joint damage identify fragments of the extracellularmatrix of cartilage (i.e. fragments of type II collagen,aggrecan and smaller proteoglycans). Identification of fragmentsof these molecules in urine or serum does not consistentlycorrelate with radiographic changes andsymptoms. Furthermore, biomarkers of type II collagenand aggrecan are not specific for the various stages ofOA, and in some cases, may not even be specific for OA.Consequently, there are no reliable assays that can informprognostic evaluations and monitor responses to therapeuticmodalities. The lack of such biomarkers has alsohampered the development of structure-modifying pharmacologicalagents for the treatment of OA. Currentpharmacological management of this disease is dominatedby analgesics, non-steroidal anti-inflammatory drugs(NSAIDs), slow-acting symptomatic drugs and intraarticularinjection of hyaluronic acid (viscosupplementation)or corticosteroids. Analgesics and NSAIDs arecommonly administrated to all patients, irrespective of thestage of the disease. However, clinical trials have shownthat only 20 to 60 percent of patients actually respond totreatment. This means that many patients will not benefitfrom the drugs that are administered. Also, long-term useof analgesics and NSAIDs is associated with adverse reactionsand gastro-intestinal side effects. Therefore, identificationof more sensitive biomarkers of pre-radiographicjoint tissue turnover have the capacity to reflect diseaserelevant biological activity and provide useful diagnosticand therapeutic information, enabling a more rational,targeted and individualized approach to disease management.The recent proliferation of post-genomic technologieshas resulted in rapid growth and progress in biomarkerresearch. Current research on OA biomarkers focuses onidentification of biomarkers in urine, serum and synovialfluid using approaches including proteomics, metabolomics,lipidomics, advanced imaging techniques, genomics, epigenomicsand transcriptmoics and bioinformatics. This presentationwill discuss how these technologies are currentlybeing applied to identify early biomarkers of joint inflammationand tissue damage using 2-D and 3-D culture systemsand translating the information for the benefit of humanpatients. There is considerable interest in developing “combinationbiomarkers” that include biochemical, immunologic,genetic and imaging data. It is anticipated that“combination biomarkers” will have the diagnostic andprognostic power to predict responses to pharmaceuticalagents and non-pharmacological therapies and facilitatepatient sub-classification/stratification strategies to increasehomogeneity in study and treatment groups. However,the availability of tools and reagents is a major bottleneck inthe biomarker pipeline, which has consequences for thedevelopment of disease-modifying osteoarthritis drugs(DMOADs).