Collagen and Bone Strength

Abstract

Bone strength is a complex property which we understand in only a limited and incomplete fashion. Bone density and bone strength are highly but imperfectly correlated.1 The relative amounts and properties of the mineral (apatite) and the organic matrix (mainly type I collagen) in bone, as well as the organization of the bone at both the microscopic and macroscopic scales (microarchitecture and anatomy, respectively), determine its mechanical strength.1-7 That there is a strong genetic component to bone density and, more generally, to bone strength is well established,8-20 but we still know relatively little about the contributions of specific genes to bone mineral content and bone strength. As we discuss below, the evidence for the importance of various candidate genes is uneven in its quality but is compelling in the case of the type I collagen genes. Readers of this journal know that bone is a metabolically active tissue, with bone resorption and deposition proceeding as ongoing processes. Bone modeling in response to load, as described by Wolff,21 enables bones to adapt their material structures to optimize both their mechanical properties and their mass. Osteoporosis in many but not all settings, including those associated with estrogen insufficiency, steroid use, nutritional abnormalities, or excessive exercise, develops when these opposing processes are unbalanced.22 Whether the cause is osteoblastic insufficiency or osteoclastic overactivity, the result at the tissue level is always a loss of bone mass/density and deleterious changes in bone architecture. At the inorganic molecular level, the smaller mineral crystals disappear, and the larger more brittle crystals persist.23 There is some suggestion that collagen structure and properties may also be altered at the organic level.24-27 In an article by Puustjärvi et al.28 on page 321 of this Journal issue, the authors probe the mechanism of bone loss associated with heavy exercise. They report that long-term running significantly reduced bone density in beagle dog vertebrae without changing the bone's mechanical (indentation) properties. The authors suggest that changes in the orientation of the collagen network, without changes in collagen maturation (cross-linking) and content (hydroxyproline per tissue), contributed to the maintenance of strength in the face of decreased mineral density. The purpose of this commentary is to review additional documentation for that view while indicating the limitations of the present study. First, we briefly review genotype-phenotype associations of collagen. Next, the impact of collagen mutations on the microscopic structure of the connective tissue are considered. Then, we summarize what is known relating these microarchitectural changes to biomechanical tests. Finally, we consider how Puustjärvi et al.'s28 paper fits into this background. The existence of a mechanistic link between type I collagen and bone strength has been amply demonstrated by an extensive literature on osteogenesis imperfecta (OI) and other clinical syndromes attributable to mutations of type I collagen genes (COLIA1) and COLIA2 (summarized on-line29, 30). Most of these data depend on family studies in which inheritance of putative pathogenic alleles could be followed. Such investigations have been able to relate the clinical severity of OI to the nature of the specific mutation present in each kindred. The range of syndromes is broad, extending from in utero death to extremely subtle manifestations, with most patients suffering disability due to multiple fractures and their consequences. This variability led to the hypothesis that some type I collagen mutations might predispose to fragility fractures or osteoporosis but might be otherwise clinically silent (e.g., Refs. 27 and 31–33).31-33 Conversely, while most OI patients demonstrate subnormal bone mineral density (BMD), some have diminished bone strength but normal BMD.34 Several mouse models of OI arising from mutations of the type I collagen genes Cola1 and Cola2 have been used for similar analyses. Naturally occurring mutants include the oim/oim mouse,35 which makes a type I collagen α1 chain trimer due to a nonsense mutation of Cola2, and the retroviral insertion Mov-13, which disrupts Cola1. While oim/oim mice model moderate to severe OI, oim/+ heterozygous mice are an excellent model of mild OI.36 Mice harboring transgenes encoding genetically engineered glycine substitutions of the type I collagen α1 model the perinatal lethal form of OI.37 Ultrastructural and biomechanical investigations of bones from these animal models6, 36, 38-41 have linked the brittleness of OI bones to abnormalities in the collagen structure. However, these biomechanical studies are limited in important ways, as discussed below. Our understanding of OI encompasses detailed information regarding the pathogenic mechanisms by which bone fragility arises in affected individuals or organisms.42-44 Among the characte