Abstract
IntroductionAging proteins undergo non-enzymatic post-translational modification, including isomerization and racemization. We hypothesized that cartilage with many long-lived components could accumulate non-enzymatically modified amino acids in the form of isomerized aspartate and that its liberation due to osteoarthritis (OA)-related cartilage degradation could reflect OA severity.MethodsArticular cartilage and synovial fluid were obtained from 14 randomly selected total knee arthroplasty cases (56 to 79 years old) and non-arthritis cartilage from 8 trauma cases (51 to 83 years old). Paired lesional cartilage and non-lesioned OA cartilage were graded histologically using a modified Mankin system. Paired cartilage and synovial fluids were assayed for isomerized aspartate, phosphate-buffered saline/EDTA (ethylenediaminetetraacetic acid) extractable glycosaminoglycans, and total protein. Macroscopically normal non-lesioned OA cartilage was separated into superficial and deep regions when cartilage thickness was at least 3 mm (n = 6).ResultsNormalized to cartilage wet weight, normal cartilage and deep non-lesioned OA cartilage contained significantly (P < 0.05) more isomerized aspartate than superficial non-lesioned OA cartilage and lesioned cartilage. Synovial fluid isomerized aspartate correlated positively (R2 = 0.53, P = 0.02) and glycosaminoglycans correlated negatively (R2 = 0.42, P = 0.04) with histological OA lesion severity. Neither synovial fluid isomerized aspartate nor glycosaminoglycans nor total protein correlated with histological scores of non-lesioned areas.ConclusionsWe show for the first time that human cartilage and synovial fluid contain measurable quantities of an isomerized amino acid and that synovial fluid concentrations of isomerized aspartate reflected severity of histological OA. Further assessment is warranted to identify the cartilage proteins containing this modification and to assess the functional consequences and biomarker applications of this analyte in OA.
Highlights
Aging proteins undergo non-enzymatic posttranslational modification, including isomerization and racemization
Neither synovial fluid isomerized aspartate nor glycosaminoglycans nor total protein correlated with histological scores of non-lesioned areas
We show for the first time that human cartilage and synovial fluid contain measurable quantities of an isomerized amino acid and that synovial fluid concentrations of isomerized aspartate reflected severity of histological OA
Summary
Aging proteins undergo non-enzymatic posttranslational modification, including isomerization and racemization. We hypothesized that cartilage with many longlived components could accumulate non-enzymatically modified amino acids in the form of isomerized aspartate and that its liberation due to osteoarthritis (OA)-related cartilage degradation could reflect OA severity As proteins age, they undergo non-enzymatic post-translational modifications leading to accumulation of these modifications in long-lived proteins that potentially can alter both their structure and their properties. The rate of amino acid modification is influenced by local conditions such as pH [4,5], temperature [6], and protein structure and conformation [710] but is dependent on the amino acid itself [1] As these changes may bring about structural alterations, they are not necessarily biologically silent as evinced by the association of racemized and isomerized amino acids in human tissues with a variety of disease states, including cataract formation, Paget disease of bone, Alzheimer disease, and UV radiation-induced skin damage [11].
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