Biomedical subjects

Stefan Judex

Publications and source records attributed to Stefan Judex.

13 recordsLinked to original sources

PubMed2006

Low-level mechanical vibrations can influence bone resorption and bone formation in the growing skeleton.

Short durations of extremely small magnitude, high-frequency, mechanical stimuli can promote anabolic activity in the adult skeleton. Here, it is determined if such signals can influence trabecular and cortical formative and resorptive activity in the growing skeleton, if the newly formed bone is of high quality, and if the insertion of rest periods during the loading phase would enhance the efficacy of the mechanical regimen. Eight-week-old female BALB/cByJ mice were divided into four groups, baseline control (n = 8), age-matched control (n = 10), whole-body vibration (WBV) at 45 Hz (0.3 g) for 15 min day(-1) (n = 10), and WBV that were interrupted every second by 10 of rest (WBV-R, n = 10). In vivo strain gaging of two additional mice indicated that the mechanical signal induced strain oscillations of approximately 10 microstrain on the periosteal surface of the proximal tibia. After 3 weeks of WBV, applied for 15 min each day, osteoclastic activity in the trabecular metaphysis and epiphysis of the tibia was 33% and 31% lower (P <0.05) than in age-matched controls. Bone formation rates (BFR.BS(-1)) on the endocortical surface of the metaphysis were 30% greater (P <0.05) in WBV than in age-matched control mice but trabecular and middiaphyseal BFR were not significantly altered. The insertion of rest periods (WBV-R) failed to potentiate the cellular effects. Three weeks of either WBV or WBV-R did not negatively influence body mass, bone length, or chemical bone matrix properties of the tibia. These data indicate that in the growing skeleton, short daily periods of extremely small, high-frequency mechanical signals can inhibit trabecular bone resorption, site specifically attenuate the declining levels of bone formation, and maintain a high level of matrix quality. If WBV prove to be efficacious in the growing human skeleton, they may be able to provide the basis for a non-pharmacological and safe means to increase peak bone mass and, ultimately, reduce the incidence of osteoporosis or stress fractures later in life.

Animals↗

PubMed2006

Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude.

There is growing evidence that extremely small mechanical signals, if applied at a sufficiently high frequency, can serve as anabolic signals to bone tissue. To determine if the responsiveness of bone to low-magnitude, high-frequency parameters is modulated by endocrine imbalance, ovariectomized (OVX) Sprague-Dawley rats were subjected to whole body vibrations (WBV, 0.15 g) at 45 Hz (n=6) or 90 Hz (n=6) for 10 min/day, and compared to OVX age-matched controls (n=6). Five additional rats were used, in vivo, to establish the induced bone surface strain magnitudes (and strain rates). Following a 28 d protocol, bone formation rates in the metaphysis of the proximal tibia were 159% greater in 90 Hz rats when compared to age-matched controls, but 45 Hz rats were not significantly different from controls. Bone morphology of 90 Hz rats indicated significantly greater trabecular bone volume (22% and 25%) and thicker trabeculae (11% and 12%) over either controls or 45 Hz rats in the epiphysis of the distal femur, respectively. Despite the enhanced sensitivity of the skeleton towards the 90 Hz signal, the strain magnitudes and strain rates induced by this frequency were significantly lower than during 45 Hz vibration, suggesting that factors other than matrix strain are driving the anabolic response. Ideally, such mechanical signals represent a non-pharmacologic means of controlling bone mass and morphology in spite of systemic pressures for bone resorption.

Animals↗

PubMed2006

Low-level mechanical signals and their potential as a non-pharmacological intervention for osteoporosis.

BACKGROUND: exercise is recognised as a critical regulatory signal to the skeletal system, but which specific aspects of exercise are responsible for influencing bone mass and morphology and resisting fractures remains unknown. Recent data indicate that extremely low-level mechanical signals are anabolic to bone, and thus may be used, non-invasively, as a form of 'passive' exercise to positively influence skeletal status. OBJECTIVE: to summarise recent experimental studies on the effect of low-level mechanical signals (hypothesised to serve as a surrogate for the spectral content of muscle contractility) as a potential non-pharmacological intervention for osteoporosis. RESULTS: low magnitude mechanical signals are anabolic to bone if applied at a high frequency (15-90 Hz). Long-term animal studies (1 year) show that these low-magnitude mechanical signals can increase cancellous bone volume fraction, trabecular thickness, trabecular number and enhance bone stiffness and strength. Studies in the mouse have shown that these low-level signals will stimulate bone formation rate and labelled surface in cortical and cancellous bone, but the molecular and genetic regulation of this mechanosensitivity is extremely complex. Preliminary studies in children with disabling conditions and post-menopausal women indicate that such signals can be efficacious in reversing and/or preventing bone loss. CONCLUSIONS: considering that the strains (deformations) that result from these low-level vibrations are far below (<1/1000th) those which may cause damage to the bone, we believe they represent a unique, non-pharmacological prophylaxis for osteoporosis. Given that so many physiologic systems are tuned to specific frequencies, such as sight, hearing and touch, it should not be entirely surprising that the musculoskeletal system would be responsive to frequency as well.

Animals↗

PubMed2006

Low-level, high-frequency mechanical signals enhance musculoskeletal development of young women with low BMD.

UNLABELLED: The potential for brief periods of low-magnitude, high-frequency mechanical signals to enhance the musculoskeletal system was evaluated in young women with low BMD. Twelve months of this noninvasive signal, induced as whole body vibration for at least 2 minutes each day, increased bone and muscle mass in the axial skeleton and lower extremities compared with controls. INTRODUCTION: The incidence of osteoporosis, a disease that manifests in the elderly, may be reduced by increasing peak bone mass in the young. Preliminary data indicate that extremely low-level mechanical signals are anabolic to bone tissue, and their ability to enhance bone and muscle mass in young women was investigated in this study. MATERIALS AND METHODS: A 12-month trial was conducted in 48 young women (15-20 years) with low BMD and a history of at least one skeletal fracture. One half of the subjects underwent brief (10 minutes requested), daily, low-level whole body vibration (30 Hz, 0.3g); the remaining women served as controls. Quantitative CT performed at baseline and at the end of study was used to establish changes in muscle and bone mass in the weight-bearing skeleton. RESULTS: Using an intention-to-treat (ITT) analysis, cancellous bone in the lumbar vertebrae and cortical bone in the femoral midshaft of the experimental group increased by 2.1% (p = 0.025) and 3.4% (p < 0.001), respectively, compared with 0.1% (p = 0.74) and 1.1% (p = 0.14), in controls. Increases in cancellous and cortical bone were 2.0% (p = 0.06) and 2.3% (p = 0.04) greater, respectively, in the experimental group compared with controls. Cross-sectional area of paraspinous musculature was 4.9% greater (p = 0.002) in the experimental group versus controls. When a per protocol analysis was considered, gains in both muscle and bone were strongly correlated to a threshold in compliance, where the benefit of the mechanical intervention compared with controls was realized once subjects used the device for at least 2 minute/day (n = 18), as reflected by a 3.9% increase in cancellous bone of the spine (p = 0.007), 2.9% increase in cortical bone of the femur (p = 0.009), and 7.2% increase in musculature of the spine (p = 0.001) compared with controls and low compliers (n = 30). CONCLUSIONS: Short bouts of extremely low-level mechanical signals, several orders of magnitude below that associated with vigorous exercise, increased bone and muscle mass in the weight-bearing skeleton of young adult females with low BMD. Should these musculoskeletal enhancements be preserved through adulthood, this intervention may prove to be a deterrent to osteoporosis in the elderly.

Adolescent↗

PubMed2005

Mechanical modulation of molecular signals which regulate anabolic and catabolic activity in bone tissue.

Identifying the molecular mechanisms that regulate bone's adaptive response to alterations in load bearing may potentiate the discovery of interventions to curb osteoporosis. Adult female mice (BALB/cByJ) were subjected to catabolic (disuse) and anabolic (45 Hz, 0.3g vibration for 10 min/day) signals, and changes in the mRNA levels of thirteen genes were compared to altered indices of bone formation. Age-matched mice served as controls. Following 4 days of disuse, significant (P = 0.05) decreases in mRNA levels were measured for several genes, including collagen type I (-55%), osteonectin (-44%), osterix (-36%), and MMP-2 (-36%) all of which, after 21 days, had normalized to control levels. In contrast, expression of several genes in the vibrated group, which failed to show significant changes at 4 days, demonstrated significant increases after 21 days, including inducible nitric oxide synthase (iNOS) (39%, P = 0.07), MMP-2 (54%), and receptor activator of the nuclear factor kB ligand (RANKL) (32%). Correlations of gene expression patterns across experimental conditions and time points allowed the functional clustering of responsive genes into two distinct groups. Each cluster's specific regulatory role (formation vs. resorption) was reinforced by the 60% suppression of formation rates caused by disuse, and the 55% increase in formation rates stimulated by mechanical signals (P < 0.05). These data confirm the complexity of the bone remodeling process, both in terms of the number of genes involved, their interaction and coordination of resorptive and formative activity, and the temporal sensitivity of the processes. More detailed spatial and temporal correlations between altered mRNA levels and tissue plasticity may further delineate the molecules responsible for the control of bone mass and morphology.

Animals↗

PubMed2005

High-frequency, low-magnitude vibrations suppress the number of blood vessels per muscle fiber in mouse soleus muscle.

Extremely low-magnitude (0.3 g), high-frequency (30-90 Hz), whole body vibrations can stimulate bone formation and are hypothesized to provide a surrogate for the oscillations of muscle during contraction. Little is known, however, about the potential of these mechanical signals to stimulate adaptive responses in other tissues. The objective of this study was to determine whether low-level mechanical signals produce structural adaptations in the vasculature of skeletal muscle. Eight-week-old male BALB/cByJ (BALB) mice were divided into two experimental groups: mice subjected to low-level, whole body vibrations (45 Hz, 0.3 g) superimposed on normal cage activities for 15 min/day (n = 6), and age-matched controls (n = 7). After the 6-wk experimental protocol, sections from end and mid regions of the soleus muscles were stained with lectin from Bandeiraea Simplicifolia, an endothelial cell marker, and smooth muscle (SM) alpha-actin, a perivascular cell marker. Six weeks of this low-level vibration caused a 29% decrease in the number of lectin-positive vessels per muscle fiber in the end region of the soleus muscle, indicating a significant reduction in the number of capillaries per muscle fibers. Similarly, these vibrations caused a 36% reduction in SM alpha-actin-positive vessels per muscle fiber, indicating a reduction in the number of arterioles and venules. The decreases in lectin- and SM alpha-actin-positive vessels per muscle fiber ratios were not significant in the mid muscle sections. These results demonstrate the sensitivity of the vasculature in mouse skeletal muscle to whole body, low-level mechanical signals.

Adaptation, Physiological↗

PubMed2005

Gene expression patterns in bone after 4 days of hind-limb unloading in two inbred strains of mice.

INTRODUCTION: An improved understanding of the interdependence of transcriptional and genomic control of bone loss is critical for the design of effective and safe countermeasures for osteoporosis in space and on Earth. In an effort to test whether molecular pathways modulating the loss of functional weight bearing are dependent on genetic makeup, we quantified the differential expression of genes critical to the early stages of bone remodeling in two different strains of mice. METHODS: Adult (4-mo-old) female BALB/cByJ (BALB) and C3H/HeJ (C3H) mice, strains with different sensitivities to unloading, were subjected to hind-limb unloading (HLU) or normal cage activities. RNA was extracted from the tibia following 4 d of HLU and expression levels were determined. RESULTS: In the BALB mice, HLU significantly altered transcriptional levels of osterix (-36%), alkaline phosphatase (-36%), osteonectin (-44%), collagen type 1 (-55%), MMP2 (-36%), osteocalcin (-68%), and osteopontin (+28%). This expression pattern was highly correlated (R2 = 0.75) with altered expression levels in the C3H mice, but the magnitude of altered mRNA levels was less than half of those in the BALB mice. These strain-specific changes in gene expression were consistent with the differential changes in bone formation, as determined in a second group of BALB and C3H mice. DISCUSSION AND CONCLUSIONS: These data indicate that genetics may influence the absolute changes in gene expression of genes during spaceflight, but that the molecular pathways targeted by countermeasures of bone loss may not need to be specific to an individual's genetic makeup.

Animals↗

PubMed2004

Genetically based influences on the site-specific regulation of trabecular and cortical bone morphology.

UNLABELLED: The degree of site-specificity by which genes influence bone quantity and architecture was investigated in the femur of three strains of mice. Morphological indices were highly dependent on both genetic makeup as well as anatomical location showing that the assessment of bone structure from a single site cannot be extrapolated to other sites even within a single bone. INTRODUCTION: The identification of genes responsible for establishing peak BMD will yield critical information on the regulation of bone quantity and quality. Whereas such knowledge may eventually uncover novel molecular drug targets or enable the identification of individuals at risk of osteoporosis, the site-specificity by which putative genotypes cause low or high bone mass (and effective bone morphology) is essentially unknown. MATERIALS AND METHODS: microCT was used to determine morphological and microarchitectural features of the femora harvested from three genetically distinct strains of 4-month-old female mice, each with distinct skeletal mass (low: C57BL/6J [B6], medium: BALB/cByJ [BALB], high: C3H/HeJ [C3H]). Two trabecular regions (distal epiphysis and metaphysis) were considered in addition to four cortical regions within the metaphysis and diaphysis. RESULTS AND CONCLUSIONS: Comparing morphological properties of the different trabecular and cortical femoral regions between the three strains of mice, it was apparent that high or low values of specific parameters of bone morphology could not be consistently attributed to the same genetic strain. Trabecular metaphyseal bone volume, for instance, was 385% larger in C3H mice than in B6 mice, yet the two strains displayed similar bone volume fractions in the epiphysis. Similarly, BALB mice had 48% more trabecular bone than C3H mice in the epiphysis, but there were no strain-specific differences in cortical bone area at the diaphysis. These data suggest that the genetic control of bone mass and morphology, even within a given bone, is highly site-specific and that a comprehensive search for genes that are indicative of bone quantity and quality may also have to occur on a very site-specific basis.

Animals↗

PubMed2004

Genetically linked site-specificity of disuse osteoporosis.

UNLABELLED: The genetic influence on bone loss in response to mechanical unloading was investigated within diaphyseal and distal femoral regions in three genetically distinct strains of mice. One mouse strain failed to lose bone after removal of function, whereas osteopenia was evident in multiple regions of the remaining two strains but in different areas of the bone. INTRODUCTION: It is well recognized that susceptibility to osteoporosis is, in large measure, determined by the genome, but whether this influence is systemic or site-specific is not yet known. Here, the extent to which genetic variations influence regional bone loss caused by disuse was studied in the femora of adult female mice from three inbred strains. MATERIALS AND METHODS: Adult C57BL/6J (B6), C3H/HeJ (C3H), and BALB/cByJ (BALB) mice were subjected to 15-21 days of disuse, achieved by hindlimb suspension, and six distinct anatomical regions of the femur were analyzed by high-resolution microCT. RESULTS AND CONCLUSIONS: In B6 mice, the amount of disuse stimulated bone loss was relatively uniform across all regions, with 20% loss of trabecular bone and 10% loss of cortical bone. The degree of bone loss in BALB mice varied greatly, ranging from 59% in the metaphysis to 3% in the proximal diaphysis. In this strain, the nonuniformity of bone loss was directly related to the nonuniform distribution of baseline bone morphology (r2 = 0.94). In direct contrast with BALB and B6, disuse failed to produce significant losses of bone in any of the analyzed regions of the C3H mice. Instead, these animals displayed a unique compensatory mechanism to disuse, where the large loss of calcified tissue from the endocortical surface (-24%) was compensated for by an expansion of the periosteal envelope (10%). These data indicate a strong, yet complex, genetic dependence of the site-specific regulation of bone remodeling in response to a powerful catabolic signal. Consequently, the skeletal region of interest and the genetic make-up of the individual may have to be considered interdependently when considering the pathogenesis of osteoporosis or the efficacy of an intervention to prevent or recover bone loss.

Animals↗

PubMed2004

Genetic variations that regulate bone morphology in the male mouse skeleton do not define its susceptibility to mechanical unloading.

Genetics can substantially influence bone morphology and may define the skeleton's response to mechanical unloading. Recent data indicated that disuse produces different site-specific responses in the skeleton of genetically distinct adult female C3H/HeJ (C3H) and BALB/cByJ (BALB) mice; while disuse BALB mice had significantly less bone than age-matched controls in the distal and diaphyseal femur, the removal of weight bearing had a much smaller influence in C3H. Using adult male mice from these two inbred strains, the hypothesis was tested that interactions between genetic variations and anatomic location define bone morphology and its susceptibility to unloading. Four-month-old male BALB and C3H mice were either subjected to 21 days of hindlimb unloading or served as controls. Multiple cortical and trabecular regions within the distal and diaphyseal femur were analyzed by micro-computed tomography. C3H controls had significantly greater diaphyseal and metaphyseal cortical bone area (45% and 32%) and greater metaphyseal trabecular bone volume fraction (67%) than BALB controls, but epiphyseal trabecular bone volume fraction was similar between the two strains. Despite these substantial, site-specific differences in bone morphology, disuse induced similar changes in bone morphology in these two strains. Compared to controls, disuse BALB and C3H had significantly less metaphyseal (17% and 19%) and epiphyseal (10% and 13%) trabecular bone, while diaphyseal and metaphyseal cortical bone geometry was unaffected. These data indicate that the genetic variations that caused spatially nonuniform differences in trabecular and cortical bone morphology between the two strains had little influence on the susceptibility of a specific site to unloading. Cross-gender comparisons with previous data from female BALB and C3H mice further suggest strong interactions by which gender, genotype, and anatomical location define the response of the skeleton to the removal of weight bearing.

Animals↗

PubMed2003

Combining high-resolution micro-computed tomography with material composition to define the quality of bone tissue.

Atraumatic fractures of the skeleton in osteoporotic patients are directly related to a deterioration of bone strength. However, the failure of the bone tissue to withstand functional load bearing cannot be explained as a simple decrease in bone mineral density (quantity); strength is also significantly dependent upon bone quality. While a formal definition of bone quality is somewhat elusive, at the very least, it incorporates architectural, physical, and biologic factors that are critical to bone strength. Such factors include bone morphology (ie, trabecular connectivity, cross-sectional geometry, longitudinal curvature); the tissue's material properties (eg, stiffness, strength); its chemical composition and architecture (eg, ratio of calcium to other components of the organic and/or inorganic phase, collagen orientation, porosity, permeability); and the viability of the tissue (eg, responsivity of the bone cell population). Combining high-resolution structural indices of bone, as determined by micro-computed tomography; material properties determined by nanoindentation; and the chemical make-up of bone, as determined by infrared spectroscopy, helps to provide critical information toward a more comprehensive assessment of the interdependence of bone quality, quantity, and fracture risk.

Animals↗

PubMed2003

Adaptations of trabecular bone to low magnitude vibrations result in more uniform stress and strain under load.

Extremely low magnitude mechanical stimuli (<10 microstrain) induced at high frequencies are anabolic to trabecular bone. Here, we used finite element (FE) modeling to investigate the mechanical implications of a one year mechanical intervention. Adult female sheep stood with their hindlimbs either on a vibrating plate (30 Hz, 0.3 g) for 20 min/d, 5 d/wk or on an inactive plate. Microcomputed tomography data of 1 cm bone cubes extracted from the medial femoral condyles were transformed into FE meshes. Simulated compressive loads applied to the trabecular meshes in the three orthogonal directions indicated that the low level mechanical intervention significantly increased the apparent trabecular tissue stiffness of the femoral condyle in the longitudinal (+17%, p<0.02), anterior-posterior (+29%, p<0.01), and medial-lateral (+37%, p<0.01) direction, thus reducing apparent strain magnitudes for a given applied load. For a given apparent input strain (or stress), the resultant stresses and strains within trabeculae were more uniformly distributed in the off-axis loading directions in cubes of mechanically loaded sheep. These data suggest that trabecular bone responds to low level mechanical loads with intricate adaptations beyond a simple reduction in apparent strain magnitude, producing a structure that is stiffer and less prone to fracture for a given load.

Adaptation, Physiological↗

PubMed2002

Genetic predisposition to low bone mass is paralleled by an enhanced sensitivity to signals anabolic to the skeleton.

The structure of the adult skeleton is determined, in large part, by its genome. Whether genetic variations may influence the effectiveness of interventions to combat skeletal diseases remains unknown. The differential response of trabecular bone to an anabolic (low-level mechanical vibration) and a catabolic (disuse) mechanical stimulus were evaluated in three strains of adult mice. In low bone-mineral-density C57BL/6J mice, the low-level mechanical signal caused significantly larger bone formation rates (BFR) in the proximal tibia, but the removal of functional weight bearing did not significantly alter BFR. In mid-density BALB/cByJ mice, mechanical stimulation also increased BFR, whereas disuse significantly decreased BFR. In contrast, neither anabolic nor catabolic mechanical signals influenced any index of bone formation in high-density C3H/HeJ mice. Together, data from this study indicate that the sensitivity of trabecular tissue to both anabolic and catabolic stimuli is influenced by the genome. Extrapolated to humans, these results may explain in part why prophylaxes for low bone mass are not universally effective, yet also indicate that there may be a genotypic indication of people who are at reduced risk of suffering from bone loss.

Adaptation, Physiological↗