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Because a lack of mechanical information favors the development of adipocytes at the expense of osteoblasts, we hypothesized that the peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent balance between osteoblasts and adipocytes is affected by mechanical stimuli. We tested the robustness of this hypothesis in in vivo rodent osteogenic exercise, in vitro cyclic loading of cancellous haversian bone samples, and cyclic stretching of primary stromal and C3H10T1/2 cells. We found that running rats exhibit a decreased marrow fat volume associated with an increased bone formation, presumably through recruitment of osteoprogenitors. In the tissue culture model and primary stromal cells, cyclic loading induced higher Runx2 and lower PPARgamma2 protein levels. Given the proadipocytic and antiosteoblastic activities of PPARgamma, we studied the effects of cyclic stretching in C3H10T1/2 cells, treated either with the PPARgamma activator, Rosiglitazone, or with GW9662, a potent antagonist of PPARgamma. We found, through both cytochemistry and analysis of lineage marker expression, that under Roziglitazone cyclic stretch partially overcomes the induction of adipogenesis and is still able to favor osteoblast differentiation. Conversely, cyclic stretch has additive effects with GW9662 in inducing osteoblastogenesis. In conclusion, we provide evidence that mechanical stimuli are potential PPARgamma modulators counteracting adipocyte differentiation and inhibition of osteoblastogenesis.

Long-duration bed rest is widely employed to simulate the effects of microgravity on various physiological systems, especially for studies of bone, muscle, and the cardiovascular system. This microgravity analog is also extensively used to develop and test countermeasures to microgravity-altered adaptations to Earth gravity. Initial investigations of bone loss used horizontal bed rest with the view that this model represented the closest approximation to inactivity and minimization of hydrostatic effects, but all Earth-based analogs must contend with the constant force of gravity by adjustment of the G vector. Later concerns about the lack of similarity between headward fluid shifts in space and those with horizontal bed rest encouraged the use of 6 degree head-down tilt (HDT) bed rest as pioneered by Russian investigators. Headward fluid shifts in space may redistribute bone from the legs to the head. At present, HDT bed rest with normal volunteers is the most common analog for microgravity simulation and to test countermeasures for bone loss, muscle and cardiac atrophy, orthostatic intolerance, and reduced muscle strength/exercise capacity. Also, current physiologic countermeasures are focused on long-duration missions such as Mars, so in this review we emphasize HDT bed rest studies with durations of 30 days and longer. However, recent results suggest that the HDT bed rest analog is less representative as an analog for other important physiological problems of long-duration space flight such as fluid shifts, spinal dysfunction and radiation hazards.

Bone sialoprotein (BSP) and osteopontin (OPN) are both highly expressed in bone, but their functional specificities are unknown. OPN knockout (−/−) mice do not lose bone in a model of hindlimb disuse (tail suspension), showing the importance of OPN in bone remodeling. We report that BSP−/− mice are viable and breed normally, but their weight and size are lower than wild-type (WT) mice. Bone is undermineralized in fetuses and young adults, but not in older (≥12 mo) BSP−/− mice. At 4 mo, BSP−/− mice display thinner cortical bones than WT, but greater trabecular bone volume with very low bone formation rate, which indicates reduced resorption, as confirmed by lower osteoclast surfaces. Although the frequency of total colonies and committed osteoblast colonies is the same, fewer mineralized colonies expressing decreased levels of osteoblast markers form in BSP−/− versus WT bone marrow stromal cultures. BSP−/− hematopoietic progenitors form fewer osteoclasts, but their resorptive activity on dentin is normal. Tail-suspended BSP−/− mice lose bone in hindlimbs, as expected. In conclusion, BSP deficiency impairs bone growth and mineralization, concomitant with dramatically reduced bone formation. It does not, however, prevent the bone loss resulting from loss of mechanical stimulation, a phenotype that is clearly different from OPN−/− mice.

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ABSTRACT:We depict a fragility bone state in two primitive osteoporosis populations using 3D highresolution peripheral in vivo QCT (HR-pQCT). Postmenopausal women (C, controls, n ‫ס‬ 54; WF, wrist, n ‫ס‬ 50; HF, hip, n ‫ס‬ 62 recent fractured patients) were analyzed for lumbar and hip DXA areal BMD (aBMD), cancellous and cortical volumetric BMD (vBMD), and microstructural and geometric parameters on tibia and radius by HR-pQCT. Principal component analysis (PCA) allowed extracting factors that best represent bone variables. Comparison between groups was made by analysis of covariance (ANCOVA). Two factors (>80% of the entire variability) are extracted by PCA: at the radius, the first is a combination of trabecular parameters and the second of cortical parameters. At the tibia, we found the reverse. Femoral neck aBMD is decreased in WF (8.6%) and in HF (18%) groups (no lumbar difference). WF showed a ∼20% reduction in radius trabecular vBMD and number. Radius cortical vBMD and thickness decrease by 6% and 14%, respectively. At the tibia, only the cortical compartment is affected, with ∼20% reduction in bone area, thickness, and section modulus and 6% reduction in vBMD. HF showed same radius trabecular alterations than WF, but radius cortical parameters are more severely affected than WF with reduced bone area (25%), thickness (28.5%), and vBMD (11%). At the tibia, trabecular vBMD and number decrease by 26% and 17.5%, respectively. Tibia cortical bone area, thickness, and section modulus showed a >30% decrease, whereas vBMD reduction reached 13%. Geometry parameters at the tibia displayed the greatest differences between healthy and fractured patients and between wrist and hip fractures.

Abstract--Bone mass and microarchitecture are the main determinants of bone strength. Three-dimensional micro-computed