Breakthroughs and Views Collagen overglycosylation: A biochemical feature that may contribute to bone quality Ligia J. Dominguez b, * , Mario Barbagallo b , Luigi Moro a a Department of Biochemistry, Biophysics, and Macromolecular Chemistry, University of Trieste, Italy b Geriatric Unit, University of Palermo, Palermo, Italy Received 23 January 2005 Abstract Skeletal ability to resist mechanical stress is determined by bone amount and quality, which relies on macro- and micro-archi- tecture, turnover, bone matrix, and mineralisation; the role of collagen has not been clearly elucidated. Numerous post-translational steps are involved in collagen type I biosynthesis, including residue hydroxylation and glycosylation catalysed by enzymes that work until the protein folds forming the triple helix; therefore, folding rate regulates these processes. Overglycosylated hydroxylysines are poor substrates for e-amino group deamination which initiates cross-link formation. Three clinical conditions associated with frac- tures may relate collagen overglycosylation with bone quality: (i) Osteogenesis Imperfecta, in which genetic mutations distort triple helix conformation and slow folding rate favouring overglycosylation; (ii) diabetes mellitus, with collagen overglycosylation by AGE accumulation; and, (iii) menopause, according to experimental studies demonstrating ovariectomy-related trabecular bone collagen overglycosylation preventable by 17b-estradiol or tamoxifen. Specific actions on collagen of drugs used for bone protection should be explored in future studies. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Glycosylation; Collagen; Osteoporosis; Bone quality; Osteogenesis Imperfecta; Diabetes mellitus; Menopause The function of the skeleton, as an antigravity scaf- fold capable of resisting mechanical stress, is determined by the amount of bone and by the type of tissue struc- ture able to best exert bone resistance, generally defined as ‘‘bone quality.’’ Bone quality relies on different parameters, such as the macro-architecture, micro-ar- chitecture, turnover rate, bone matrix, and mineralisa- tion [1]. While each of these is essential for a good quality of bone, the crucial role of collagen, the main component of the bone matrix upon which all of the above-mentioned parameters depend to some extent, has not been clearly elucidated. Collagen biosynthesis and fibril formation A large number of intracellular post-translational processing steps are involved in the biosynthesis of type I procollagen. They include hydroxylation of prolyl res- idues, hydroxylation of lysyl residues, and glycosylation of some hydroxylysine residues with galactose and glucosylgalactose [2]. All the reactions are catalysed by specific enzymes that work until the protein folds into the triple-helical conformation. As a consequence, the degree of modification of the protein is regulated by its rate of folding [3] (see Fig. 1). Once the mature molecules are formed, they assemble into fibrils, the functional supramolecular structural framework. In fibrils, molecules of collagen are parallel to each other and the three strands forming the triple helix 0006-291X/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2005.02.050 * Corresponding author. Fax: +39 091 6552952. E-mail address: mabar@unipa.it (L.J. Dominguez). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 330 (2005) 1–4 BBRC