Pyridinium cross-links in bone of patients with osteogenesis imperfecta: Evidence of a normal intrafibrillar collagen packing

The brittleness of bone in patients with osteogenesis imperfecta (OI) has b een attributed to an aberrant collagen network. However, the role of collag en in the loss of tissue integrity has not been well established. To gain a n insight into the biochemistry and structure of the collagen network, the cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) and th e level of triple helical hydroxylysine (Hy1) were determined in bone of OI patients (types I, III, and IV) as well as controls. The amount of triple helical Hy1 was increased in all patients. LP levels in OI were not signifi cantly different; in contrast, the amount of HP (and as a consequence the H P/LP ratio and the total pyridinoline level) was significantly increased. T here was no relationship between the sum of pyridinolines and the amount of triple helical Hy1, indicating that lysyl hydroxylation of the triple heli x and the telopeptides are under separate control. Cross-linking is the res ult of a specific three-dimensional arrangement of collagens within the fib ril; only molecules that are correctly aligned are able to form cross-links . Inasmuch as the total amount of pyridinoline cross-links In OI bone is si milar to control bone, the packing geometry of intrafibrillar collagen mole cules is not disturbed in OI, Consequently, the brittleness of bone is not caused by a disorganized intrafibrillar collagen packing and/or loss of cro ss-links. This is an unexpected finding, because mutant collagen molecules with a random distribution within the fibril are expected to result in disr uptions of the alignment of neighboring collagen molecules. Pepsin digestio n of OI bone revealed that collagen located at the surface of the fibril ha d lower cross-link levels compared with collagen located at the inside of t he fibril, indicating that mutant molecules are not distributed randomly wi thin the fibril but are located preferentially at the surface of the fibril .