Pyridinium crosslinks

The pyridinium crosslinks, pyridinoline (Pyd) and deoxypyridinoline (Dpd), are products of a collagen crosslinking pathway involving telopeptide hydroxylysine. The hydroxylation of telopeptide lysines is a crucial step in controlling the tissue specificity of collagen crosslinking, and is now known to involve a separate enzyme to that which hydroxylates lysines destined to be in the helix [2]. The tissue specificity of crosslinking helps to provide bone specificity for pyridinium crosslink measurements because of the restricted distribution of these compounds and their absence from skin. However, the fact that bone remodelling occurs constantly and throughout life, whereas the skin turnover process is very slow, ensures that, even though skin may constitute a slightly greater proportion of the total body pool of collagen type I, any component of fibrillar collagen will preferentially be derived from bone by virtue of its higher turnover rate. Dpd has been proposed as a more specific bone marker than Pyd because of its restricted tissue distribution. Dpd is, however, present in other tissues including intramuscular collagen, vascular tissue and ligaments [3], although the much lower turnover rates of these soft tissues again ensures that their contribution to Dpd excretion is negligible.

As the formation of pyridinium crosslinks occurs extracellularly during the final stage of maturation of the collagen fibril, these compounds reflect only the degradation of mature collagen and not any biosynthetic intermediates. Their application is also facilitated by the lack of any requirements for dietary restrictions [4].

Development of urinary crosslink assays

Following studies in the early 1980s, in which the presence of collagen crosslinks in urine was established, the main interest in crosslink assays came with the development of an HPLC (high performance liquid chromatography) method applicable to measurement of pyridinium crosslinks in urine [5]. Development of an automated HPLC system including an internal standard improved the precision of the assay at least 3-fold [6]. Initially, measurements of total crosslinks were performed after acid hydrolysis of the urine. The validity of this method for assessing bone resorption was confirmed by the observed close correlation with bone histomor-phometry and with radioisotopic methods [7].

The HPLC assay was used to show that about 40% of the pyridinium crosslinks were present in urine in a free form that could be measured without the need for hydrolysis [8]. The proportion of free crosslinks was found to be relatively constant in both healthy individuals and in patient groups with osteoporosis, thyroid disorders, hyperparathyroidism and arthritic diseases. These observations paved the way for the development of direct immunoassays that initially measured both Pyd and Dpd along with small molecular weight substances (Mr < 1000). This was followed by the commercial development of specific monoclonal antibody-based assays that measure the more bone-specific crosslink, Dpd [9]. More recently, immunoassays for free urinary Dpd have become widely available on several types of automated immunoassay analyzers in reference laboratories and clinical laboratories.

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