Part of “CHAPTER 56 – MARKERS OF BONE METABOLISM“

Bone is composed of ˜70% mineral and 30% organic matter. The mineral, primarily in the form of hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂] crystals, is embedded in and aligned with the collagen fibrils, which play an important role in crystal formation. This calcium-collagen composite ensures the two main functions of bone: providing a structural framework and acting as a reservoir for mineral ions.

The organic phase of bone is made of cells and a protein matrix, of which ˜90% is collagen type I. Bone also contains a large number of different proteins, glycoproteins, and proteoglycans, many of which are negatively charged (Table 56-3). Although their precise functions are not established, these noncollagenous proteins are probably associated with the organization and mineralization of the skeletal matrix.

Collagen is synthesized by osteoblasts as a larger precursor molecule. This “procollagen” molecule contains the triple helix portion, which bears several hydroxyproline residues, and globular extensions at the N- and the C-terminal ends (i.e., N- and C-terminal propeptides). After secretion of the collagen molecule, these propeptides are removed en bloc by specific proteases at the cell surface. The C-terminal propeptide remains intact and appears as a 100-kDa protein in the blood. The helical collagen molecules spontaneously assemble into fibrils, which are then covalently cross-linked to impart the necessary tensile strength. This process is initiated extracellularly through the action of a single enzyme, lysyl oxidase. Thereafter, reactions of the lysine-derived aldehydes occur spontaneously and culminate in the formation of trifunctional pyridinium cross-links (Fig. 56-1). Unlike hydroxyproline, which is already present in the newly synthesized protein, the pyridinium cross-links are found exclusively in mature collagens of the established extracellular matrix. Of the two cross-link analogs produced, deoxypyridinoline is located primarily in bone collagen. Pyridinoline occurs in cartilage and other soft tissues as well as in bone (see Chap. 189).