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Systems analysis of bone

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Abstract The genetic variants contributing to variability in skeletal traits have been well studied, and several hundred quantitative trait loci (QTLs) have been mapped and several genes contributing to trait variation have been identified. However, many questions remain unanswered. In particular, it is unclear whether variation in a single gene leads to alterations in function. Bone is a highly adaptive system and genetic variants affecting one trait are often accompanied by compensatory changes in other traits. The functional interactions among traits, which is known as phenotypic integration, has been observed in many biological systems, including bone. Phenotypic integration is a property of bone that is critically important for establishing a mechanically functional structure that is capable of supporting the forces imparted during daily activities. In this paper, bone is reviewed as a system and primarily in the context of functionality. A better understanding of the system properties of bone will lead to novel targets for future genetic analyses and the identification of genes that are directly responsible for regulating bone strength. This systems analysis has the added benefit of leaving a trail of valuable information about how the skeletal system works. This information will provide novel approaches to assessing skeletal health during growth and aging and for developing novel treatment strategies to reduce the morbidity and mortality associated with fragility fractures. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease

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The “Funnel Effect” represents the large number of biological and genetic pathways that lead to a skeletal structure that is more susceptible to fracturing. These and other biological pathways present tremendous heterogeneity in the underlying genetic basis of fragility.

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Variation in phenotypic integration during growth may lead to different sets of adult traits that contribute to fracture risk in different ways: via reduced strength and/or reduced toughness. Risk will depend on bone size and the degree to which covariation was altered.

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Recombinant inbred (RI) mouse strains derived from A/J and B6 inbred mouse strains can be used to study functional interactions among bone traits. If bone does not possess biological processes that covary traits then each member of the RI panel will exhibit a random set of traits. However, if bone possesses biological processes that covary traits in a highly ordered way then each member of the RI panel will exhibit a set of traits that is well adapted to weight‐bearing loading demands. An examination of the traits across the panel will thus reveal the nature of this covariation.

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Bone slenderness varies widely among individuals, independent of height, and could lead to significant reductions in bone stiffness and strength if not compensated.

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Femoral mid‐shafts grow by expanding and drifting simultaneously, as shown by the fluorescent labels in the histological cross section. Expansion of each surface involves a mathematical relationship between bone formed and bone resorbed on the outer (sub‐periosteal) and inner (endosteal) surfaces. Regulating periosteal expansion (ΔTtAr) and marrow expansion (ΔMaAr) so that cortical area matches loading demands involves the coordination of osteoblastic and osteoclastic cell populations working on two surfaces.

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A review of the literature revealed that over 350 quantitative trait loci (QTLs) have been identified for mouse bone. QTLs have been identified for many traits, including (a) bone mineral density, (b) bone morphology, and (c) bone mechanical properties. The graph shows the fraction of identified QTL as a function of chromosomal location.

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Bone tissue exhibits a highly organized microstructure. (a) Cortical bone is composed of a field of osteons interspersed amidst interstitial tissue. (b) Trabecular bone comprises packets of lamellar tissue.

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Whole bone mechanical function is defined by morphological traits and tissue‐level mechanical properties. Each trait category can be further reduced to a large number of traits that can be readily measured for genetic analyses. The traits listed are representative of a larger list of possible traits.

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A 3‐dimensional tomographic rendering of a mouse femur reveals the complexity of bone structure. Each bone comprises a hard dense outer shell called cortical bone and a sponge‐like material called trabecular bone.

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