Little is known about osteonal bone mineral and matrix properties, although these properties are of major importance for the understanding of bone alterations related to age and bone diseases such as osteoporosis. During aging, bone undergoes modifications that compromise their structural integrity as shown clinically by the increase of fracture incidence with age. Based on Fourier transform infrared (FTIR) analysis from baboons between 0 and 32 yr of age, consistent systematic variations in bone properties as a function of tissue age are reported within osteons. The patterns observed were independent of animal age and positively correlated with bone tissue elastic behavior measured by nano-indentation. As long as tissue age is expressed as a percentage of the entire osteon radius, osteonal analyses can be used to characterize disease changes independent of the size of the osteon. These mineral and matrix analyses can be used to explain bone fragility. The mineral content (mineral-to-matrix ratio) was correlated with the animal age in both old (interstitial) and newly formed bone tissue, showing for the first time that age-related changes in BMC can be explain by an alteration in the mineralization process itself and not only by an imbalance in the remodeling process.

A major challenge for understanding susceptibility to common human diseases is determining genetic and environmental factors that influence mechanisms underlying variation in disease-related traits. The most common diseases afflicting the US population are complex diseases that develop as a result of defects in multiple genetically controlled systems in response to environmental challenges. Unraveling the etiology of these diseases is exceedingly difficult because of the many genetic and environmental factors involved. Studies of complex disease genetics in humans are challenging because it is not possible to control pedigree structure and often not practical to control environmental conditions over an extended period of time. Furthermore, access to tissues relevant to many diseases from healthy individuals is quite limited. The baboon is a well-established research model for the study of a wide array of common complex diseases, including dyslipidemia, hypertension, obesity, and osteoporosis. It is possible to acquire tissues from healthy, genetically characterized baboons that have been exposed to defined environmental stimuli. In this review, we describe the genetic and physiologic similarity of baboons with humans, the ability and usefulness of controlling environment and breeding, and current genetic and genomic resources. We discuss studies on genetics of heart disease, obesity, diabetes, metabolic syndrome, hypertension, osteoporosis, osteoarthritis, and intrauterine growth restriction using the baboon as a model for human disease. We also summarize new studies and resources under development, providing examples of potential translational studies for targeted interventions and therapies for human disease.

We hypothesize that variability in knee subchondral bone surface geometry will differentiate between patients at risk and those not at risk for developing osteoarthritis (OA) and suggest that statistical shape modeling (SSM) methods form the basis for developing a diagnostic tool for predicting the onset of OA. Using a subset of clinical knee MRI data from the osteoarthritis initiative (OAI), the objectives of this study were to (1) utilize SSM to compactly and efficiently describe variability in knee subchondral bone surface geometry and (2) determine the efficacy of SSM and rigid body transformations to distinguish between patients who are not expected to develop osteoarthritis (i.e. Control group) and those with clinical risk factors for OA (i.e. Incidence group). Quantitative differences in femur and tibia surface geometry were demonstrated between groups, although differences in knee joint alignment measures were not statistically significant, suggesting that variability in individual bone geometry may play a greater role in determining joint space geometry and mechanics. SSM provides a means of explicitly describing complete articular surface geometry and allows the complex spatial variation in joint surface geometry and joint congruence between healthy subjects and those with clinical risk of developing or existing signs of OA to be statistically demonstrated.

Quantitative genetic analyses of bone data for 710 inter-related individuals 8-85 yr of age found high heritability estimates for BMC, bone area, and areal and volumetric BMD that varied across bone sites. Activity levels, especially time in moderate plus vigorous activity, had notable effects on bone. In some cases, these effects were age and sex specific.Introduction: Genetic and environmental factors play a complex role in determining BMC, bone size, and BMD. This study assessed the heritability of bone measures; characterized the effects of age, sex, and physical activity on bone; and tested for age-and sex-specific bone effects of activity. Materials and Methods: Measures of bone size and areal and volumetric density (aBMD and vBMD, respectively) were obtained by DXA and pQCT on 710 related individuals (466 women) 8-85 yr of age. Measures of activity included percent time in moderate + vigorous activity (%ModVig), stair flights climbed per day, and miles walked per day. Quantitative genetic analyses were conducted to model the effects of activity and covariates on bone outcomes. Results: Accounting for effects of age, sex, and activity levels, genes explained 40-62% of the residual variation in BMC and BMD and 27-75% in bone size (all p < 0.001). Decline in femoral neck (FN), hip, and spine aBMD with advancing age was greater among women than men (age-by-sex interaction; all p Յ 0.05). %ModVig had the most notable effect on bone; high activity was associated with higher aBMD at all sites, but the magnitude of this effect varied. Activity among men was associated with higher FN BMC and crosssectional area (CSA) at the 4% radius, but this was not observed among women (sex-by-activity interaction, both p Յ 0.05). Younger women had greater cortical vBMD (Cort-vBMD) than younger men, with minimal difference between low and high activity levels. Influence of activity was greater in older women: older women with low activity had lower Cort-vBMD than older men, but older women with high activity had higher Cort-vBMD than older men (age-by-sex-by-activity interaction, p ‫ס‬ 0.04). Conclusions: High heritability estimates for DXA and pQCT measures varied across bone sites. Percent time spent in moderate to vigorous activity had the most notable effect on bone, and in some cases, this effect was age or sex specific.

Material property changes in bone tissue with ageing are a crucial missing component in our ability to understand and predict age-related fracture. Cortical bone osteons contain a natural gradient in tissue age, providing an ideal location to examine these effects. This study utilized osteons from baboons aged 0 to 32 years (n=12 females), representing the baboon lifespan, to examine effects of tissue and animal age on mechanical properties and composition of the material. Tissue mechanical properties (indentation modulus and hardness), composition (mineral-to-matrix ratio, carbonate substitution, and crystallinity), and aligned collagen content (aligned collagen peak height ratio) were sampled along three radial lines in three osteons per sample by nanoindentation, Raman spectroscopy, and second harmonic generation microscopy, respectively. Indentation modulus, hardness, mineral-to-matrix ratio, carbonate substitution, and aligned collagen peak height ratio followed biphasic relationships with animal age, increasing sharply during rapid growth before leveling off at sexual maturity. Mineral-to-matrix ratio and carbonate substitution increased 12% and 6.7%, respectively, per year across young animals during growth, corresponding with a nearly 7% increase in stiffness and hardness. Carbonate substitution and aligned collagen peak height ratio both increased with tissue age, increasing 6 to 12% across the osteon radii. Indentation modulus most strongly correlated with mineral-to-matrix ratio, which explained 78% of the variation in indentation modulus. Overall, the measured compositional and mechanical parameters were the lowest in tissue of the youngest animals. These results demonstrate that composition and mechanical function are closely related and influenced by tissue and animal age.

Five of the bones that characteristically comprise the cranial vault articulate on the lateral aspect of the skull at or near the cephalometric landmark referred to as the pterion. The pattern of articulation in the sutures associated with these bones varies among and within primate species and has been used as a criterion for classification in taxonomic studies, as well as in archeological and forensic studies. Within species, the sutural patterns found within the region of the pterion have remarkable consistency, which lead to the hypothesis that these patterns have a genetic basis. Sutural pattern variations were investigated at the pterion in 422 skulls from 66 rhesus monkey families with known genealogies from the long-standing colony on Cayo Santiago. Four specific types of articulation patterns were recorded. The results demonstrated that the most common suture pattern at the pterion of Cayo Santiago rhesus monkeys (86%; similar to that seen in some other anthropoid species but not humans and some apes) was characterized by an articulation between the temporal bone and parietal bone. Articulation between the sphenoid and parietal bones (type SP) accounted for 14% of the specimens and was concentrated in a dozen families. Mothers with the SP phenotype had a high incidence of offspring with SP phenotypes. Most non-SP mothers having SP offspring had siblings or family members from previous generations with the SP type. This is the first study to examine variation in sutural patterns at the pterion in pedigrees. Variation of sutural patterns shows familial aggregation, suggesting that this variation is heritable. Future work will be focused on defining the inheritance patterns of variation at the pterion, with the ultimate objective of identifying the specific genes involved and their mechanism of action.

Linkage analysis based on identity-by-descent allele-sharing can be used to identify a chromosomal region harboring a quantitative trait locus (QTL), but lacks the resolution required for gene identification. Consequently, linkage disequilibrium (association) analysis is often employed for fine-mapping. Variance-components based combined linkage and association analysis for quantitative traits in sib pairs, in which association is modeled as a mean effect and linkage is modeled in the covariance structure has been extended to general pedigrees (quantitative transmission disequilibrium test, QTDT). The QTDT approach accommodates data not only from parents and siblings, but also from all available relatives. QTDT is also robust to population stratification. However, when population stratification is absent, it is possible to utilize even more information, namely the additional information contained in the founder genotypes. In this paper, we introduce a simple modification of the allelic transmission scoring method used in the QTDT that results in a more powerful test of linkage disequilibrium, but is only applicable in the absence of population stratification. This test, the quantitative trait linkage disequilibrium (QTLD) test, has been incorporated into a new procedure in the statistical genetics computer package SOLAR. We apply this procedure in a linkage/association analysis of an electrophysiological measurement previously shown to be related to alcoholism. We also demonstrate by simulation the increase in power obtained with the QTLD test, relative to the QTDT, when a true association exists between a marker and a QTL.

Thyroid hormones play major roles in the regulation of a wide range of metabolic and physiologic processes, but the genes and environmental factors that affect normal, quantitative variation in thyroid hormone concentrations are largely unknown. Using quantitative genetic methods, we evaluated the effects of genes and environmental factors on thyroid hormone variation in 586 women and 425 men from 27 randomly ascertained Mexican-American families from the San Antonio Family Heart Study. Data were available on free and total T(4), free and total T(3), TSH, thyroglobulin, and T(4)-binding globulin, as well as on covariates, including sex, age, weight, lifestyle habits, physical activity, and others. These covariates accounted for 2-18% of total phenotypic variation, whereas genes accounted for 26-64% of the variation. Overall, free T(3) had the highest heritability, which is noteworthy because it is the most biologically active thyroid hormone and accounts for the vast majority of metabolic and physiologic effects of thyroid hormones. Our results indicate that genes account for a substantial portion of variation in human thyroid hormone levels, and suggest that further studies to identify the genes involved in this variation could reveal important insights into the processes that govern thyroid-mediated metabolism.