Steven A. Goldstein

Type I collagen mutation alters the strength and fatigue behavior of Mov13 cortical tissue

Despite advances in understanding the molecular basis of Osteogenesis Imperfecta, the mechanisms by which type I collagen mutations compromise whole bone function are not well understood. Previously, we have shown that a heterozygous type I collagen mutation is associated with increased brittleness of long bones from Mov13 transgenic mice, a model of the mild form of Osteogenesis Imperfecta. In the current study, we investigated tissue-level damage processes by testing the hypothesis that the fatigue properties of Mov13 tissue were significantly compromised relative to littermate controls. We also quantified tissue structure and mineral content to explain variations in the fatigue behavior. Micro-beam specimens were machined from the anterior and posterior quadrants of Mov13 and control femurs and subjected to cyclic bending at one of four stress levels. Mov13 tissue exhibited a 22-25% reduction in tissue bending strength and a similar reductions in fatigue life and the stress level at which damage was apparent. These results provided tissue-level evidence that damage accumulation mechanisms were significantly compromised in Mov13 cortical tissue. Given that significant alterations in tissue structure were observed in Mov13 femurs, the results of this study support the idea that Mov13 femurs were brittle because alterations in tissue structure associated with the mutation interfered with normal damage processes. These results provide new insight into the pathogenesis of Osteogenesis Imperfecta and are consistent with bone behaving as a damaging composite material, where damage accumulation is central to bone fracture.

A murine skeletal adaptation that significantly increases cortical bone mechanical properties. Implications for human skeletal fragility.

Mov13 mice carry a provirus that prevents transcription initiation of the alpha 1(I) collagen gene. Mutant mice homozygous for the null mutation produce no type I collagen and die at mid-gestation, whereas heterozygotes survive to adulthood. Dermal fibroblasts from heterozygous mice produce approximately 50% less type I collagen than normal littermates, and the partial deficiency in collagen production results in a phenotype similar to osteogenesis imperfecta type I (an inherited form of skeletal fragility). In this study, we have identified an adaptation of Mov13 skeletal tissue that significantly improves the bending strength of long bone. The adaptive response occurred over a 2-mo period, during which time a small number of newly proliferated osteogenic cells produced a significant amount of matrix components and thus generated new bone along periosteal surfaces. New bone deposition resulted in a measurable increase in cross-sectional geometry which, in turn, led to a dramatic increase in long bone bending strength.

Biomechanics of Bone

The composition and structural integrity of the human skeleton have uniquely evolved, reflecting its need to balance four major functions: protection of vital organs, mechanical support and locomotion, mineral homeostasis, and hematopoiesis. During the past century numerous investigators have carefully attempted to document the mechanical and architectural properties of bone. These studies have provided insight into potential mechanisms of bone remodeling and also contributed to the assessment of fracture risk under normal, aging, or disease conditions.

OUR UNDERSTANDING OF INHERITED SKELETAL FRAGILITY AND WHAT THIS HAS TAUGHT US ABOUT BONE STRUCTURE AND FUNCTION

Publisher Summary This chapter presents the current ideas about the molecular pathogenesis of the human inherited disease osteogenesis imperfecta (OI). OI type I is a mild disorder characterized by bone fracture without deformity, blue sclerae, normal or near-normal stature, and autosomal dominant inheritance. Osteopenia is associated with an increased rate of long bone fracture upon ambulation. For reasons not well understood, fracture frequency decreases dramatically at puberty and during young adult life but increases once again in late middle age. In contrast, OI types II–IV represent a spectrum of more severe disorders associated with a shortened life-span. OI type II, the perinatal lethal form, is characterized by short stature, a soft calvarium, blue sclerae, fragile skin, a small chest, floppy-appearing lower extremities, fragile tendons and ligaments, bone fracture with severe deformity, and death in the perinatal period because of respiratory insufficiency.