Hydroxyproline and Collagen Metabolism: Clinical Implications: Combined Clinical Staff Conference at the National Institutes of Health

Abstract

Because of Its unique occurrence in collagen, hydroxyproline is a specific and convenient basis for assessing collagen. A cell-free system from chick-embryo homogenates converted proline-C14 to collagen-bound hydroxyproline-C14; under anaerobic conditions proline was incorporated into a hydroxyproline-deficient collagen precursor associated with microsomes. In the presence of O2, a microsomal proline hydroxylase and ascorbic acid, proline residues in the collagen precursor were converted to hydroxyproline. Proline hydroxylation manipulation may be a means of affecting collagen synthesis. Over 95% of human urine hydroxyproline was bound in peptides of a composition consistent with their origin from collagen. A gelatin-free diet minimized daily variations in urinary hydroxyproline at an average of 26.3 mg/day [plus or minus] 12.8 ([plus or minus] 2 S.D.) in 40 normal adults. Marked elevations were found in growing children and patients with active acromegaly. After growth ceased or when acromegaly was treated, urine hydroxyproline returned to normal, without further change. Elevated urinary hydroxyproline levels occurred in patients with hyperthyroidism or hyperparathyroidism, in normal subjects given thyroid hormone or parathyroid extract and in other conditions affecting bone; low values were found in myxedema patients. Urinary hydroxyproline and its response to Ca infusion can be measured as bone metabolism and parathyroid activity indices. Urinary hydroxyproline is elevated in some scleroderma or dermatomyositis cases but not in other "collagen disorders". A hydroxyproline-containing protein (hypro-protein) was identified in human plasma (80% total plasma hydroxyproline); a specific procedure developed for its assay was compared with established hydroxyproline measurement methods. The chemical behavior of this protein indicated a large molecule; resistance to enzymatic digestion suggested it may be collagen or a macromolecular precursor. Hypro-protein levels were remarkably constant in 101 normal subjects of various ages. The highest and most consistent elevated levels occurred in Hodgkin''s disease, Sjogren''s syndrome, and various febrile and inflammatory disorders. The potential significance of plasma hypro-protein as an accessible index of collagen metabolism in man was discussed.