We are interested in determining if the skeleton has diminished responsiveness to mechanical loading with age. We are subjecting young-adult and aged mice to two types of loading: 1) high-amplitude, low-frequency tibial compression, and 2) low-amplitude, high-frequency whole-body vibration (WBV). These studies will clarify whether or not there is reduced mechanoresponsiveness in the aged/osteoporotic skeleton.
We are characterizing the skeletal response to damaging loading, with a focus on woven bone formation and associated changes in vascularity and gene expression. We refined the rat forelimb compression model to produce several levels of sub-fracture bone damage using either fatigue or creep displacement. We discovered that the osteogenic response to fatigue loading is proportional to the level of damage, with increasing amounts of woven bone formed with increasing damage (dose-response). In the first week after loading, woven bone area increases, leading to a partial recovery of bone strength; in the second week, the woven bone area is unchanged but it becomes denser and more mineralized, leading to full recovery of strength. We then determined that static creep loading that generates damage also induces a woven bone dose-response, indicating that damage is the predominant stimulus for the woven bone response seen in skeletal fatigue. In terms of vascular changes, both vessel area and number increase prior to increases in bone area, and their spatial distribution matched the subsequent pattern of bone formation. Angiogenic genes (e.g., VEGF) are upregulated 1 hr after fatigue loading, and BMP-2 is localized to vascular cells at this early time. Other known osteogenic genes (e.g., BSP, Osx) are then upregulated starting on day 1. Thus, vascular responses occurred in the immediate stages after fatigue loading, followed by osteogenesis.
In collaboration with Professor Jim Cheverud of the Dept. of Anatomy and Neurobiology we are examining dietary and genetic factors affecting bone mass, morphology, and biomechanical properties and the relationships of these features to obesity and leptin in mice. We are utilizing an established mouse model for obesity, diabetes, and dietary response, the cross of LG/J and SM/J mouse strains. We are measuring the level of heritability for bone traits (e.g., cortical area, trabecular bone volume, femoral strength) and their genetic correlations with obesity and leptin levels in the LGXSM Recombinant Inbred (RI) strains (N=512) and Advanced Intercross (AI) Line (N =1000). Animals have been fed either a high or low fat diet allowing us to examine the effects of both genes and environment (dietary fat) on bone characteristics and bone-obesity relationships. We will identify genomic regions (Quantitative Trait Loci, QTLs) affecting bone and its relationship to obesity. Our goal is to identify novel genes and physiological pathways affecting osteoporosis and examine how genetic and environmentally-based obesity affects bone mass, morphology and biomechanical function.
In collaboration with Professor David Ornitz we are examining the role of FGFs in post-natal bone formation induced by mechanical loading. The importance of FGF signaling in skeletal biology is illustrated by the large number of missense mutations in the genes encoding FGF receptors (FGFRs) 1, 2 and 3 that are the etiology of many human craniosynostosis and chondrodysplasia syndromes. Furthermore, loss of function and skeletal-specific conditional loss of function mutations in mouse FGFRs 1,2 and 3 also show specific defects in skeletal development and in the structure and integrity of adult bone. In contrast to our increasing understanding of the function of FGFRs in skelatogenesis, there is little information on the FGF ligands that regulate skeletal development, growth, remodeling, vasculogenesis and repair. We will test the hypothesis that in response to mechanical load, FGF signaling is required for cortical bone formation and associated increased periosteal vascularization.
