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Steven A Goldstein

Publications and source records attributed to Steven A Goldstein.

At least 19 recordsLinked to original sources
PubMed2006

Age-dependent microdamage removal following mechanically induced microdamage in trabecular bone in vivo.

In order to examine the potential age-related response of trabecular bone to microdamage, a novel animal model utilizing a bone chamber to load existing distal femoral trabecular bone of rats was developed. Fifteen 8-month-old (mature) and fifteen 24-month-old (old) Fischer Brown Norway rats underwent bilateral insertion of the bone chamber. After a 3-week recovery period, one leg per animal underwent damage-inducing loading. Double fluorochrome labeling was used to identify microcracks induced by loading. A greater crack density was found in loaded trabecular bone than in corresponding unloaded control bone at day 0 in both age groups (mature n=5, old n=4). At day 35 post loading, older rats (n=3) had greater crack density (suggesting little removal of microcracks), whereas younger rats (n=5) had no difference between loaded and unloaded limbs, suggesting induced microcracks were removed. The difference in bone volume fraction between the loaded and unloaded limb were significantly different at 21 and 35 days post loading when comparing the old with the mature rats. The data suggest a reduced ability of bone to recover after damage in the older rats. The damage-inducing capabilities of the animal model were demonstrated using double fluorochrome labeling in vivo for detection of microcracks. The results indicate that removal of microdamage is altered with age.

Aging↗
PubMed2006

Quantitative trait loci modulate vertebral morphology and mechanical properties in a population of 18-month-old genetically heterogeneous mice.

The aim of this study was to examine effects of polymorphic genes on vertebral bone morphology and mechanical properties. Genotypes from 525 18-month-old female mice were compared to geometric traits obtained from micro-computed tomography and mechanical properties from compression testing. Genetic markers were associated with traits on at least 13 different chromosomes, demonstrating the complexity of genetic control over vertebral form, function and aging.

Aging↗
PubMed2006

Bone tissue compositional differences in women with and without osteoporotic fracture.

It is generally accepted that the hallmark of osteoporosis is a reduction in bone mass. There is significant overlap, however, in bone mineral density between osteoporotic and normal individuals. This study examined the chemical composition of bone tissue obtained from women who had sustained a fracture and women without fracture to determine if there are differences between the two groups. Nineteen fractured and eleven non-fractured proximal femurs were obtained, matched for age and bone volume fraction obtained from micro-computed tomography. Trabecular bone specimens were examined by Raman spectroscopy to determine measures of chemical composition. A subset of the specimens was utilized to compare locations at the fracture and regions at least 2 mm away from apparent tissue damage using Raman spectroscopy. In addition, fifteen iliac crest biopsies each were obtained from women who had sustained a fracture and from normal controls. Raman spectroscopy was used to determine measures of chemical composition of trabecular and cortical bone. The results demonstrated that femoral bone tissue in the region of visible damage had a trend towards differences compared to regions at least 2 mm from visible damage. Femoral trabecular bone in fractured women had a higher carbonate/amide I area ratio than in unfractured women. Iliac crest biopsies revealed a higher carbonate/phosphate ratio in cortical bone from women who had sustained a fracture. Results suggest that the chemical composition of bone tissue may be an additional risk factor for osteoporotic fracture.

Aged↗
PubMed2006

Novel explant model to study mechanotransduction and cell-cell communication.

To understand in situ behavior of osteocytes, we characterized a model of osteocytes in their native bone matrix and demonstrated real-time biologic activity of osteocytes while bending the bone matrix. Using 43 male Sprague-Dawley rats, dumbbell-shaped explants were harvested from stainless steel femoral implants after 6-12 weeks and incubated in culture medium or fixed. Sixteen specimens were used to determine bone volume density (BV/TV), volumetric bone mineral density (BMD) and histology for different implantation periods. Osteocyte viability was evaluated by L-lactate dehydrogenase (LDH) activity in 12 cultured explants. Confocal microscopy was used to assess tracer diffusion in three explants and changes in osteocyte pH of a mechanically loaded explant. From 6 to 12 weeks, explant BV/TV and volumetric BMD trended up 92.5% and 101%, respectively. They were significantly and highly correlated. Tissues were uniformly intramembranous and all bone cell types were present. Explants maintained LDH activity through culture day 8. Diffusion at 200 microM was limited to 1,209 Da. Explants appeared capable of reproducing complex bone biology. This model may be useful in understanding osteocyte mechanotransduction in the context of a physiologically relevant bone matrix.

Animals↗
PubMed2006

Procollagen C proteinase enhancer 1 genes are important determinants of the mechanical properties and geometry of bone and the ultrastructure of connective tissues.

Procollagen C proteinases (pCPs) cleave type I to III procollagen C propeptides as a necessary step in assembling the major fibrous components of vertebrate extracellular matrix. The protein PCOLCE1 (procollagen C proteinase enhancer 1) is not a proteinase but can enhance the activity of pCPs approximately 10-fold in vitro and has reported roles in inhibiting other proteinases and in growth control. Here we have generated mice with null alleles of the PCOLCE1 gene, Pcolce, to ascertain in vivo roles. Although Pcolce-/- mice are viable and fertile, Pcolce-/- male, but not female, long bones are more massive and have altered geometries that increase resistance to loading, compared to wild type. Mechanical testing indicated inferior material properties of Pcolce-/- male long bone, apparently compensated for by the adaptive changes in bone geometry. Male and female Pcolce-/- vertebrae both appeared to compensate for inferior material properties with thickened and more numerous trabeculae and had a uniquely altered morphology in deposited mineral. Ultrastructurally, Pcolce-/- mice had profoundly abnormal collagen fibrils in both mineralized and nonmineralized tissues. In Pcolce-/- tendon, 100% of collagen fibrils had deranged morphologies, indicating marked functional effects in this tissue. Thus, PCOLCE1 is an important determinant of bone mechanical properties and geometry and of collagen fibril morphology in mammals, and the human PCOLCE1 gene is identified as a candidate for phenotypes with defects in such attributes in humans.

Alleles↗
PubMed2006

Tissue engineering solutions for traumatic bone loss.

Tissue engineering strategies for the repair, replacement, or augmentation of bone defects involves the use of cells, matrices, and bioregulatory factors. The source (endogenous, exogenous) and character of these factors, however, may vary greatly among the many approaches taken by current investigators. Although the results of current tissue engineering methods for regenerating bone have shown great promise, the extent of damage to extremities associated with war injuries may require the development of techniques that differ substantially from current practice.

Bone Regeneration↗
PubMed2005

Anabolic actions of PTH (1-34): use of a novel tissue engineering model to investigate temporal effects on bone.

PTH is in clinical use for the treatment of osteoporosis and is under intensive investigation for its potential in applications of tissue engineering, fracture healing, and implant integration. However, the mechanisms of its action to stimulate bone formation are still unclear. A novel bone tissue engineering model was used to elucidate basic mechanisms of PTH anabolic actions. Ectopic ossicles containing cortical bone, trabecular bone, and a hematopoietic marrow were generated from implanted bone marrow stromal cells (BMSC). One week after implantation, nude mice were administered PTH or vehicle for 1 week (group 1), 3 weeks (group 2), or 7 weeks (group 3). Another group was also treated for 3 weeks, initiated 12 weeks after implantation (group 4). Micro-radiography and histomorphometry revealed increased marrow cellularity in group 1 PTH-treated ossicles, increased bone in group 2 PTH-treated ossicles, and similar amounts of bone in both group 3 and 4 ossicles regardless of treatment. Incidence of phosphate mineral and phosphate mineral to hydroxyproline ratio via Raman spectroscopy were significantly higher after 3 weeks versus 1 week of PTH treatment, but there was no difference between PTH- and vehicle-treated ossicles. Early events of PTH action in group 1 ossicles and the effects of a single injection of PTH on 1- and 2-week-old ossicles were evaluated by Northern blot analysis. Osteocalcin (OC) mRNA was increased after 1 week of intermittent PTH treatment in ossicles and calvaria but an acute injection did not alter OC mRNA. In contrast, a single injection of PTH increased matrix gamma-carboxyglutamic acid protein (MGP) mRNA in 2-week-old ossicles. Differential and temporal-dependent effects of PTH on OC and MGP suggest at the molecular level, that PTH acts to inhibit osteoblast mineralization. However, this does not translate into tissue level alterations. These data indicate that anabolic actions of PTH in ectopic ossicles are temporally dependent on the BMSC implanted and suggest that cell implantation strategies are particularly responsive to PTH.

Adipocytes↗
PubMed2005

A simple method for stem cell labeling with fluorine 18.

Hexadecyl-4-[(18)F]fluorobenzoate ([(18)F]HFB), a long chain fluorinated benzoic acid ester, was prepared in a one-step synthesis by aromatic nucleophilic substitution of [(18)F]fluoride ion on hexadecyl-4-(N,N,N-trimethylammonio)benzoate. The radiolabeled ester was obtained in good yields (52% decay corrected) and high purity (97%). [(18)F]HFB was used to radiolabel rat mesenchymal stem cells (MSCs) by absorption into cell membranes. MicroPET imaging of [(18)F]HFB-labeled MSCs following intravenous injection into the rat showed the expected high and persistent accumulation of radioactivity in the lungs. [(18)F]HFB is thus simple to prepare and uses labeling agent for short-term distribution studies of injected stem cells.

Animals↗
PubMed2005

In vivo assessment of regenerate axial stiffness in distraction osteogenesis.

This paper presents an in vivo test for assessment of regenerate axial stiffness after the distraction phase of lengthening therapy. The test result supplements radiography in evaluating bone healing and assists in determining when the regenerate stiffness is sufficient for removal of the external fixator. The test is non-invasive and does not require fixator removal. The theoretical basis for the method is that an externally applied load is shared between the fixator and the regenerating bone. The amount of load carried by the regenerate depends on its axial stiffness, which increases with advanced mineralization. By measuring the force in the fixator while applying a known external load to the limb, the load-share ratio between fixator and limb can be assessed. A load-share ratio of 100% indicates that the entire load is carried by the fixator. The ratio decreases as the regenerate structure gradually stiffens. In a clinical trial of 22 individuals with tibial lengthening, the fixator was removed when the load-share ratio dropped below 10%. None of the patients experienced fracture after removal of the fixator.

Biomechanical Phenomena↗
PubMed2005

An application of nanoindentation technique to measure bone tissue Lamellae properties.

Measuring the microscopic mechanical properties of bone tissue is important in support of understanding the etiology and pathogenesis of many bone diseases. Knowledge about these properties provides a context for estimating the local mechanical environment of bone related cells thait coordinate the adaptation to loads experienced at the whole organ level. The objective of this study was to determine the effects of experimental testing parameters on nanoindentation measures of lamellar-level bone mechanical properties. Specifically, we examined the effect of specimen preparation condition, indentation depth, repetitive loading, time delay, and displacement rate. The nanoindentation experiments produced measures of lamellar elastic moduli for human cortical bone (average value of 17.7 +/- 4.0 GPa for osteons and 19.3 +/- 4.7 GPa for interstitial bone tissue). In addition, the hardness measurements produced results consistent with data in the literature (average 0.52 +/- 0.15 GPa for osteons and 0.59 +/- 0.20 GPa for interstitial bone tissue). Consistent modulus values can be obtained from a 500-nm-deep indent. The results also indicated that the moduli and hardnesses of the dry specimens are significantly greater (22.6% and 56.9%, respectively) than those of the wet and wet and embedded specimens. The latter two groups were not different. The moduli obtained at a 5-nm/s loading rate were significantly lower than the values at the 10- and 20-nm/s loading rates while the 10- and 20-nm/s rates were not significantly different. The hardness measurements showed similar rate-dependent results. The preliminary results indicated that interstitial bone tissue has significantly higher modulus and hardness than osteonal bone tissue. In addition, a significant correlation between hardness and elastic modulus was observed.

Aged↗
PubMed2004

Quantitative trait loci that modulate femoral mechanical properties in a genetically heterogeneous mouse population.

UNLABELLED: The goal of this study was to investigate genetic effects on mechanical properties of the mouse femur. We found evidence for QTL on eight chromosomes that affect mechanical traits. Some of these QTL may have primary effects on body weight or femoral geometry, and others seem to affect bone quality directly. INTRODUCTION: Previous studies have shown a dependence of fragility-related fracture risk on genetic background. Although many of these studies investigated the effect of genetics on BMD, basic measures of bone geometry and mechanical integrity may provide a more comprehensive characterization of the genetic effects on bone fragility. The purpose of this study was to identify quantitative trait loci (QTL) that affect mechanical and material properties of cortical bone in a genetically heterogeneous mouse population. MATERIALS AND METHODS: A total of 486 female UM-HET3 mice was used for this study. UM-HET3 mice are produced as the offspring of (BALB/cJ x C57BL/6J) F(1) females and (C3H/HeJ x DBA/2J) F(1) males. Femurs from 18-month-old mice were tested to failure in four-point bending to assess mechanical properties of cortical bone; these properties were compared with genotype data from 185 biallelic loci. A permutation-based test was used to detect significant associations between genetic markers and mechanical traits. This test generates p values that account for the effect of testing multiple hypotheses. Throughout the experiment, p < or = 0.05 was considered statistically significant. Analysis of covariance was used to examine possible effects of body weight and femoral geometry. RESULTS: We found evidence for genes on maternal chromosomes 11 and 13 and paternal chromosomes 2, 4, 7, 10, 11, and 17 that affect mechanical and material properties of femoral bone. The total variance explained by genetic effects on each mechanical trait ranges from 2.9% to 15.4%. Most of the identified polymorphisms influence mechanical traits even after adjustment for body weight. Adjustment for femoral geometry reduces the effects of some of the QTL, but those on chromosomes 2 and 10 do not seem to be influenced by femoral geometry. CONCLUSIONS: Many genes and chromosomes are involved in the genetic control over mechanical integrity of cortical bone. QTL on paternal chromosomes 4 and 11 may mediate mechanical properties, at least in part, by modulation of femoral geometry. Other QTL identified here may directly affect bone tissue quality.

Animals↗
PubMed2004

Brittle IV mouse model for osteogenesis imperfecta IV demonstrates postpubertal adaptations to improve whole bone strength.

UNLABELLED: The Brtl mouse model for type IV osteogenesis imperfecta improves its whole bone strength and stiffness between 2 and 6 months of age. This adaptation is accomplished without a corresponding improvement in geometric resistance to bending, suggesting an improvement in matrix material properties. INTRODUCTION: The Brittle IV (Brtl) mouse was developed as a knock-in model for osteogenesis imperfecta (OI) type IV. A Gly349Cys substitution was introduced into one col1a1 allele, resulting in a phenotype representative of the disease. In this study, we investigate the effect of the Brtl mutation on whole bone architecture, strength, and composition across a range of age groups. MATERIALS AND METHODS: One-, 2-, 6-, and 12-month-old Brtl and wildtype (WT) mice were analyzed. Femurs were assessed at the central diaphysis for cortical geometric parameters using microCT and were subsequently mechanically tested to failure by four-point bending. Matrix material properties were predicted using microCT data to normalize data from mechanical tests. Raman spectroscopy and DXA were used to assess matrix composition. RESULTS: Our findings show a postpubertal adaptation in which Brtl femoral strength and stiffness increase through a mechanism independent of changes in whole bone geometry. These findings suggest an improvement in the material properties of the bone matrix itself, rather than improvements in whole bone geometry, as seen in previous mouse models of OI. Raman spectroscopic results suggest these findings may be caused by changes in mineral/matrix balance rather than improvements in mineral crystallinity. CONCLUSIONS: Our findings parallel the currently unexplained clinical observation of decreased fractures in human OI patients after puberty. The Brtl mouse remains an important tool for investigating therapeutic interventions for OI.

Adaptation, Physiological↗
PubMed2004

Osteocyte lacuna size and shape in women with and without osteoporotic fracture.

Osteocytes have been hypothesized to control the amount and location of bone tissue which is resorbed or formed, based on the strain magnitude they perceive, and therefore may play a role in the bone loss of osteoporosis. The shape of osteocyte lacunae influences the mechanical strain applied to the osteocyte; thus, it is important to quantify their shape to further understand the mechanical environment of this cell. Previous studies of the size and shape of lacunae have been contradictory and limited to two-dimensional measurements on iliac crest biopsies. This investigation measured the size and shape of osteocyte lacunae in trabecular bone near a typical fracture site from three-dimensional image sets obtained by confocal microscopy. Bone tissue specimens were obtained from individuals undergoing hip replacement subsequent to fracture, and matched cadaveric specimens without fracture. After extensive image processing to differentiate the lacunae from the matrix, the volume and anisotropy of the lacuna were determined. No significant difference was found in the size (volume) or shape (anisotropy) of the lacunae between women with and without osteoporotic fracture, although there was a large range of sizes and shapes in both groups. These results suggest that the size or shape of the lacunae, which influences the strain in osteocytes, does not play a role in osteoporotic fracture. In addition, this study provides geometric measures of lacunae that are important in computational modeling of the mechanical environment of osteocytes.

Aged↗
PubMed2004

Earliest mineral and matrix changes in force-induced musculoskeletal disease as revealed by Raman microspectroscopic imaging.

UNLABELLED: Craniosynostosis, premature fusion of the skull bones at the sutures, is the second most common human birth defect in the skull. Raman microspectroscopy was used to examine the composition, relative amounts, and locations of the mineral and matrix produced in mouse skulls undergoing force-induced craniosynostosis. Raman imaging revealed decreased relative mineral content in skulls undergoing craniosynostosis compared with unloaded specimens. INTRODUCTION: Raman microspectroscopy, a nondestructive vibrational spectroscopic technique, was used to examine the composition, relative amounts, and locations of the mineral and matrix produced in mouse skulls undergoing force-induced craniosynostosis. Craniosynostosis, premature fusion of the skull bones at the sutures, is the second most common birth defect in the face and skull. The calvaria, or flat bones that comprise the top of the skull, are most often affected, and craniosynostosis is a feature of over 100 human syndromes and conditions. MATERIALS AND METHODS: Raman images of the suture, the tips immediately adjacent to the suture (osteogenic fronts), and mature parietal bones of loaded and unloaded calvaria were acquired. Images were acquired at 2.6 x 2.6 microm spatial resolution and ranged in a field of view from 180 x 210 microm to 180 x 325 microm. RESULTS AND CONCLUSIONS: This study found that osteogenic fronts subjected to uniaxial compression had decreased relative mineral content compared with unloaded osteogenic fronts, presumably because of new and incomplete mineral deposition. Increased matrix production in osteogenic fronts undergoing craniosynostosis was observed. Understanding how force affects the composition, relative amounts, and location of the mineral and matrix provides insight into musculoskeletal disease in general and craniosynostosis in particular. This is the first report in which Raman microspectroscopy was used to study musculoskeletal disease. These data show how Raman microspectroscopy can be used to study subtle changes that occur in disease.

Animals↗
PubMed2004

A comparative study of mini-external fixation systems used to treat unstable metacarpal fractures.

We compared the biomechanical properties, clinical versatility, application ease, and financial cost of 7 mini-external fixation systems used to treat unstable metacarpal shaft fractures with segmental bone loss. Attached to a maple dowel fracture model, each fixator was tested in axial compression, lateral 4-point bending, 45 degrees apex-dorsal 4-point bending, and torsion. The EBI DynaFix system had the highest overall rigidity values and was highly versatile; the Synthes/AO Mini-External Fixator had intermediate rigidity values and was the lightest system tested; the Howmedica Mini-Hoffmann fixator was substantially less rigid than all the other tested constructs but was the most versatile. Devices constructed with polymethylmethacrylate and Kirschner wires were rigid, lightweight, and inexpensive. Routine use of these devices is discouraged, however, because of unacceptable loosening at the pin-cement interface during testing and because of difficulties encountered during construction and application. None of the external fixation systems tested was superior in all the parameters analyzed.

Biomechanical Phenomena↗
PubMed2003

Focal adhesion kinase expression during mandibular distraction osteogenesis: evidence for mechanotransduction.

Distraction osteogenesis is an established treatment strategy in the reconstruction of the craniofacial skeleton. The underlying mechanisms that drive bone formation during this process are largely unknown, but a regulatory role for mechanical force is believed to be critical. The integrin-mediated signal transduction cascade is a primary pathway by which signal transduction of mechanical stimuli (i.e., mechanotransduction) occurs. Focal adhesion kinase (FAK) is a significant regulator in this pathway. The authors hypothesize that mechanical forces created during distraction osteogenesis are responsible for the osteogenic response that takes place, and that these changes arise through integrin-dependent mechanotransduction. Using a rat model of distraction osteogenesis, the authors examined the expression of FAK in critical size defects (n = 15), subcritical size defects (n = 15), and mandibles undergoing distraction osteogenesis (n = 15). Their findings demonstrated FAK immunolocalization in mandibles undergoing distraction osteogenesis, but not in the critical size defects or in subcritical size defects, despite varying degrees of bone formation in the latter two groups. Furthermore, bone sialoprotein mRNA in situ hybridization patterns were found to mirror FAK immunolocalization patterns in mandibles undergoing distraction osteogenesis, demonstrating an association of FAK expression with the osteogenic process specific to distraction osteogenesis. These findings suggest that the bone formation in distraction osteogenesis is regulated by mechanical force by means of integrin-dependent mechanotransduction pathways.

Animals↗
PubMed2003

Quantitative trait loci for femoral size and shape in a genetically heterogeneous mouse population.

UNLABELLED: The aim of this study was to examine the genetic effects on cortical bone geometry. Genotypes from 487 mice were compared with geometric traits obtained from microCT. We found 14 genetic markers that associate with geometric traits, showing the complexity of genetic control over bone geometry. INTRODUCTION: Previous studies have shown that genetic background affects bone characteristics, particularly bone mineral density, in both mouse and human populations. Much less is known, however, about the effects of polymorphic genes on bone size, shape, and mechanical integrity. In this study, we investigated the genetic determinants of geometric properties of cortical bone in mice. MATERIALS AND METHODS: This study used a genetically heterogeneous mouse population, which is denoted UM-HET3 stock and is derived as the progeny of (BALB/cJ X C57BL/6J) F1 females and (C3H/HeJ X DBA/2J) F1 males. The experimental group consisted of 487 female UM-HET3 mice. Genotypic data from 99 polymorphic genetic loci was obtained from the mice at 4 weeks of age. At 18 months of age, the mice were humanely killed, and the right femurs were scanned with microcomputed tomography to assess geometric properties of cortical bone. A permutation-based test was used to detect significant associations between genetic markers and geometric traits. This test generates experiment-wise p values, which account for the effect of testing multiple hypotheses. An experiment-wise p < or = 0.05 was considered statistically significant. RESULTS: Fourteen genetic markers were found to significantly associate with one or more geometric traits. Two markers (D3Mit62 and D4Mit155) were associated with traits describing bone size; 2 (D12Mit167 and D14Mit170) were linked with traits describing bone shape; and 10 (D1Nds2, D5Mit95, D6Mit216, D7Mit91, D8Mit51, D9Mit110, D11Mit83, D15Mit100, D15Mit171, and D17Mit46) were associated with both size and shape. CONCLUSIONS: Our results indicate that the genetic control of cortical bone geometry is complex and that femoral size and shape may be influenced by different, although overlapping, groups of polymorphic loci.

Animals↗