Diss.--Belgrade. / At head of title: Acta medica Iugoslavica (Beograd), v. 12 (Supplementum 1), pp. 43, 1958. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Supervisor: Lynn Rew. Vita. Includes bibliographical references.

Thesis (M.S.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 29-32). Also available on the World Wide Web.

Introduction: The role of muscle forces in determining bone micro-architecture and strength in children is poorly understood as limited evidence relies on surrogate measures of muscle force such as muscle size. The objective of this thesis was to explore the role of muscle area, peak forces from neuromuscular performance tests and physical activity in determining bone properties at the radius and tibia in children. Methods: 37 boys and 42 girls (mean age 10.5; SD 1.6y) had their dominant forearm and lower leg imaged using peripheral quantitative computed tomography (pQCT) and high resolution pQCT (HR-pQCT). Bone mass, density, area and estimated strength were assessed. Muscle area was determined from the pQCT scans and grip strength measured via a handheld dynamometer. Peak force from a single maximal push-up performed on force platforms and the number of standard push-ups completed in a single attempt were recorded. Countermovement and standing long jump maximal forces were recorded, impulse and power were calculated, and average standing long jump distance was measured. Physical activity was measured using the Physical Activity Questionnaire for Children. Sex, maturation (estimated age from peak height velocity), weight and limb length (ulna and tibia) were controlled in the linear regression models. Variance predicted (R2) by models using muscle area, neuromuscular performance measures as independent predictors (squared partial r) of bone properties are reported. Results: Grip strength and muscle area independently predicted 14-18% of the variance in bone area at the distal radius and 9-22% of the variance in bone strength at the distal and shaft sites of radius. Peak push-up force predicted 10% of the variance in trabecular number at the distal radius. Muscle area independently predicted 5-28% and countermovement and standing long jump forces and impulses predicted 6-10% of the variance in bone area, cortical content or density at the tibia shaft. Standing long jump power predicted 5-8% of the variance in bone area and cortical density at the tibia shaft. Physical activity predicted 9% of the variance in trabecular number at the distal tibia. Discussion: Thesis findings support the use of muscle area as a surrogate for muscle forces and identified neuromuscular performance measures that will guide targeted exercise interventions aiming to optimize bone strength development in children.

The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have recently identified bone as an endocrine organ possessing the capabilities to regulate both energy metabolism and reproduction. Preliminary data suggested that Phosphatase, Orphan 1 (PHOSPHO1) a bone specific phosphatase, indispensable for bone mineralisation, may crosstalk with osteotesticular protein tyrosine phosphatase (OST-PT, Esp), a signalling molecule that dephosphorylates the insulin receptor (InsR) on the osteoblast, negatively regulating the osteoblast insulin signalling cascade. The work of this thesis has expanded upon preliminary data confirming that Esp was up-regulated 60-fold in Phospho1-/- osteoblasts. Furthermore in silico analysis revealed Phospho1 ablation is significantly associated with insulin dependent diabetes mellitus. These data form the basis of this thesis examining the role of PHOSPHO1 in energy metabolism. Initial in vivo characterisation of Phospho1-/- mice revealed that the ablation of Phospho1 results in decreased blood glucose levels, improved insulin sensitivity and glucose tolerance in juvenile, adult and aged mice. Following high fat feeding, Phospho1 ablation conferred a remarkable degree of protection against diet-induce-dobesity and non-alcoholic fatty liver disease (NAFLD) despite the 60-fold increase in Esp expression. The metabolic protection observed in Phospho1-/- mice served to strengthen PHOSPHO1’s potential role in energy metabolism. However the mechanisms remained unclear. Mice overexpressing Esp specifically in osteoblasts are glucose intolerant and insulin resistant, due to the negative regulation of osteoblast-insulin-signalling, resulting in decreased undercarboxylated osteocalcin (GLU13-OCN) release. This thesis identified however that the serum levels of a GLU13-OCN were normal in Phospho1-/- mice suggesting that there was a GLU13-OCN-independent mechanism for PHOSPHO1 regulated energy metabolism. Moreover, mass spectrometry analysis identified > 100 differentially expressed proteins in Phospho1-/- serum associated with the regulation of glycolysis and gluconeogenesis. These candidates displayed an enrichment for microRNA Mir34a and the transcription factor hepatocyte nuclear factor 1, both reported to regulate hepatic glucose homeostasis. These data therefore support the notion that further, yet undefined osteoblast derived factors contribute to whole body energy metabolism and highlight a new and unconventional role of Esp suggestive that it may act as a fine controller of insulin sensitivity in mice, offering protection from severe hypoglycaemia and dyslipidaemia. Finally, this thesis also explored the notion that decreased levels of choline may contribute to the insulin sensitivity observed in Phospho1-/- mice. Phosphocholine (PCho) is a recognised substrate for PHOSPHO1 being hydrolysed into choline and inorganic phosphate (Pi). Phosphatase Orphan 1 deficient mice, hypothesised to have reduced choline levels were fed a 2% choline rich diet; mice displayed a normalisation in insulin sensitivity and fat mass. These data suggest that Phospho1- deficiency improves the metabolic profile of mice in vivo and confers resistance to obesity and diabetes via the alteration of serum/tissue choline levels. The work described herein has characterised the metabolic phenotype of Phospho1-/- mice and began to unravel the mechanisms underlying the improved metabolic phenotype in Phospho1-/- mice.

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The principal objective of the research was to model the outflow results of multiple tracer outflow dilution (M.T.O.D.) techniques from the canine tibia so as to obtain a more precise understanding of the physiological mechanisms underlying mineral exchange in bone. To date, M.T.O.D. techniques have been performed on the tibiae of greyhound dogs but the subsequent outflow results have produced information mainly at the capillary level for the diffusible tracers concerned such as capillary permeability-surface area PSC products from the widely used Crone-Renkin formulation. Back diffusion and heterogeneous capillary flow rates lacking from the formulation, however, have impaired the accuracy of PS(C). Outflow results from two series of previously performed M.T.O.D. experiments were modelled. In the first experimental series, outflow results from the ipsilateral femoral vein concerning l25l-albumin reference and 85Sr (Ca analogue), 86Rb (K analogue) diffusible tracers were used ; the tracers having being injected into the tibial nutrient arteries. In the second experimental series, 125l-albumin and 85Sr outflow results were used from parathyroidectomised dogs in which both tracers had been injected together before and after a dose of 0.0005 mg bovine parathyroid hormone (PTH). The problem of back diffusion was alleviated by optimising a homogeneous flow model to M.T.O.D. data. The model produced informative parameter estimates for 85Sr and 86Rb concerning fluid spaces and associated boundaries in Haversian systems largely comprising the diaphyseal cortex. Exchange was assumed to take place there by virtue of injecting the tracers into the tibial nutrient artery. Blood flow rates, known to be influential in governing the extent of tracer exchange in the diaphysis, were investigated using the microsphere technique. Flow rate heterogeneity was found to be substantial, as adjudged by distributions of relative deposition densities of microspheres in 40 pieces of cortex and 10 marrow samples in 6 tibiae. For the cortex, the distributions were positively skewed with a relative dispersion of around 40%. Additional work involving light microscopy suggested that the distribution of cortical flow rates were not attributable to particular changes in capillary density, which were relatively uniform at 2682 + 510 capillaries/cm2 (4 tibiae ; 240 observations). The findings concerning flow rate heterogeneity, together with the deduction that the cortex and marrow respectively received 65% and 35% of tibial nutrient artery flow, prompted the development of a parallel multicapillary model in which 4 capillary systems were alloted to the cortex and 1 such system to the marrow. Input to the model was a suitable form of the reference tracer outflow profile which describes the large vessel transport behaviour assumed identical for all tracers concerned. Parameter estimates (mean + s.d.) found by optimisation for 85Sr and 86Rb (n=6) were PSC = 0.045 + 0.021 and 0.047 + 0.022 ml/s respectively. Apparent volumes of distribution (n=5) for the interstitial fluid were 0.90 + 0.36 (85Sr) and 0.69 + 0.22 ml of diaphysis (86Rb). Additional studies involving gamma variates showed that model inputs were robust in terms of varying degrees of large vessel dispersion. Furthermore, simulation studies involving the effect of asymmetric transport on the resulting parameter estimates in the context of modelling the PTH data provided speculative evidence for the concept of a bone-lining cell membrane controlling uptake to bone surfaces.

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