Search PubMed⌕ Search

Biomedical subjects

Stuart J Warden

Publications and source records attributed to Stuart J Warden.

At least 19 recordsLinked to original sources
PubMed2026

Fractures are highly correlated with bone density and inversely correlated with bone turnover markers in autosomal dominant osteopetrosis.

Autosomal dominant osteopetrosis (ADO) is a rare osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, which results in impaired osteoclastic bone resorption. Penetrance is incomplete, and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline BMD and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z-scores for both volumetric (r&#xa0;=&#x2009;0.87, p&#xa0;<&#x2009;.001) and areal BMD (aBMD) of the LS, and Z-scores for FN, and TH aBMD (r&#xa0;=&#x2009;0.77 to 0.78; p&#xa0;<&#x2009;.001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r&#xa0;=&#x2009;0.52, p&#xa0;=&#x2009;.004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r&#xa0;=&#x2009;-0.60, p&#xa0;<&#x2009;.001) and urine N-telopeptide/creatinine ratio (r&#xa0;=&#x2009;-0.35, p&#xa0;=&#x2009;.047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD, and bone turnover markers were similar when limited to the 37 adults with disease-causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures, or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.

Humans↗
PubMed2007

Exercise when young provides lifelong benefits to bone structure and strength.

UNLABELLED: Short-term exercise in growing rodents provided lifelong benefits to bone structure, strength, and fatigue resistance. Consequently, exercise when young may reduce the risk for fractures later in life, and the old exercise adage of "use it or lose it" may not be entirely applicable to the skeleton. INTRODUCTION: The growing skeleton is most responsive to exercise, but low-trauma fractures predominantly occur in adults. This disparity has raised the question of whether exercised-induced skeletal changes during growth persist into adulthood where they may have antifracture benefits. This study investigated whether brief exercise during growth results in lifelong changes in bone quantity, structure, quality, and mechanical properties. MATERIALS AND METHODS: Right forearms of 5-week-old Sprague-Dawley rats were exercised 3 days/week for 7 weeks using the forearm axial compression loading model. Left forearms were internal controls and not exercised. Bone quantity (mineral content and areal density) and structure (cortical area and minimum second moment of area [I(MIN)]) were assessed before and after exercise and during detraining (restriction to home cage activity). Ulnas were removed after 92 weeks of detraining (at 2 years of age) and assessed for bone quality (mineralization) and mechanical properties (ultimate force and fatigue life). RESULTS: Exercise induced consistent bone quantity and structural adaptation. The largest effect was on I(MIN), which was 25.4% (95% CI, 15.6-35.3%) greater in exercised ulnas compared with nonexercised ulnas. Bone quantity differences did not persist with detraining, whereas all of the absolute difference in bone structure between exercised and nonexercised ulnas was maintained. After detraining, exercised ulnas had 23.7% (95% CI, 13.0-34.3%) greater ultimate force, indicating enhanced bone strength. However, exercised ulnas also had lower postyield displacement (-26.4%; 95% CI, -43.6% to -9.1%), indicating increased brittleness. This resulted from greater mineralization (0.56%; 95% CI, 0.12-1.00%), but did not influence fatigue life, which was 10-fold greater in exercised ulnas. CONCLUSIONS: These data indicate that exercise when young can have lifelong benefits on bone structure and strength, and potentially, fracture risk. They suggest that the old exercise adage of "use it or lose it" may not be entirely applicable to the skeleton and that individuals undergoing skeletal growth should be encouraged to perform impact exercise.

Animals↗
PubMed2006

Segmental bone regeneration using a load-bearing biodegradable carrier of bone morphogenetic protein-2.

Segmental defect regeneration has been a clinical challenge. Current tissue-engineering approach using porous biodegradable scaffolds to delivery osteogenic cells and growth factors demonstrated success in facilitating bone regeneration in these cases. However, due to the lack of mechanical property, the porous scaffolds were evaluated in non-load bearing area or were stabilized with stress-shielding devices (bone plate or external fixation). In this paper, we tested a scaffold that does not require a bone plate because it has sufficient biomechanical strength. The tube-shaped scaffolds were manufactured from poly(propylene) fumarate/tricalcium phosphate (PPF/TCP) composites. Dicalcium phosphate dehydrate (DCPD) were used as bone morphogenetic protein-2 (BMP-2) carrier. Twenty-two scaffolds were implanted in 5mm segmental defects in rat femurs stabilized with K-wire for 6 and 15 weeks with and without 10 microg of rhBMP-2. Bridging of the segmental defect was evaluated first radiographically and was confirmed by histology and micro-computer tomography (microCT) imaging. The scaffolds in the BMP group maintained the bone length throughout the duration of the study and allow for bridging. The scaffolds in the control group failed to induce bridging and collapsed at 15 weeks. Peripheral computed tomography (pQCT) showed that BMP-2 does not increase the bone mineral density in the callus. Finally, the scaffold in BMP group was found to restore the mechanical property of the rat femur after 15 weeks. Our results demonstrated that the load-bearing BMP-2 scaffold can maintain bone length and allow successfully regeneration in segmental defects.

Animals↗
PubMed2006

Low-amplitude, broad-frequency vibration effects on cortical bone formation in mice.

Mechanical loading of the skeleton is necessary to maintain bone structure and strength. Large amplitude strains associated with vigorous activity typically result in the greatest osteogenic response; however, data suggest that low-amplitude, broad-frequency vibration results in new bone formation and may enhance adaptation through a stochastic resonance (SR) phenomenon. That is, random noise may maximally enhance bone formation to a known osteogenic stimulus. The aims of this study were to (1) assess the ability of different vibration signals to enhance cortical bone formation during short- and long-term loading and (2) determine whether vibration could effect SR in bone. Two studies were completed wherein several osteogenic loading waveforms, with or without an additive low-amplitude, broad-frequency (0-50 Hz) vibration signal, were applied to the mouse ulna in axial compression. In study 1, mice were loaded short-term (30 s/day, 2 days) with either a carrier signal alone (1 or 2 N sine waveform), vibration signal alone [0.1 N or 0.3 N root mean square (RMS)] or combined carrier and vibration signal. In study 2, mice were loaded long-term (30 s/day, 3 days/week, 4 weeks) with a carrier signal alone (static or sine waveform), vibration signal alone (0.02 N, 0.04 N, 0.08 N or 0.25 N RMS) or combined carrier and vibration signal. Sequential calcein bone labels were administered at 2 and 4 days and at 4 and 29 days after the first day of loading in study 1 and 2, respectively; bone formation parameters and changes in geometry were measured. Combined application of the carrier and vibration signals in study 1 resulted in significantly greater bone formation than with either signal alone (P < 0.001); however, this increase was independently explained by increased strain levels associated with additive vibration. When load and strain levels were similar across loading groups in study 2, cortical bone formation and changes in geometry were not significantly altered by vibration. Vibration alone did not result in any new bone formation. Our data suggest that low-amplitude, broad-frequency vibration superimposed onto an osteogenic waveform or vibration alone does not enhance cortical bone adaptation at the frequencies, amplitudes and loading periods tested.

Animals↗
PubMed2006

The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment.

The cell surface receptor, low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass. Loss-of-function mutations in LRP5 cause the human skeletal disease osteoporosis-pseudoglioma syndrome, an autosomal recessive disorder characterized by severely reduced bone mass and strength. We investigated the role of LRP5 on bone strength using mice engineered with a loss-of-function mutation in the gene. We then tested whether the osteogenic response to mechanical loading was affected by the loss of Lrp5 signaling. Lrp5-null (Lrp5-/-) mice exhibited significantly lower bone mineral density and decreased strength. The osteogenic response to mechanical loading of the ulna was reduced by 88 to 99% in Lrp5-/- mice, yet osteoblast recruitment and/or activation at mechanically strained surfaces was normal. Subsequent experiments demonstrated an inability of Lrp5-/- osteoblasts to synthesize the bone matrix protein osteopontin after a mechanical stimulus. We then tested whether Lrp5-/- mice increased bone formation in response to intermittent parathyroid hormone (PTH), a known anabolic treatment. A 4-week course of intermittent PTH (40 microg/kg/day; 5 days/week) enhanced skeletal mass equally in Lrp5-/- and Lrp5+/+ mice, suggesting that the anabolic effects of PTH do not require Lrp5 signaling. We conclude that Lrp5 is critical for mechanotransduction in osteoblasts. Lrp5 is a mediator of mature osteoblast function following loading. Our data suggest an important component of the skeletal fragility phenotype in individuals affected with osteoporosis-pseudoglioma is inadequate processing of signals derived from mechanical stimulation and that PTH might be an effective treatment for improving bone mass in these patients.

Anabolic Agents↗
PubMed2006

Low-intensity pulsed ultrasound accelerates and a nonsteroidal anti-inflammatory drug delays knee ligament healing.

BACKGROUND: Low-intensity pulsed ultrasound and nonsteroidal anti-inflammatory drugs are used to treat ligament injuries; however, their individual and combined effects are not established. HYPOTHESES: Low-intensity pulsed ultrasound accelerates ligament healing, a nonsteroidal anti-inflammatory drug delays healing, and the nonsteroidal anti-inflammatory drug inhibits the beneficial effect of low-intensity pulsed ultrasound. STUDY DESIGN: Controlled laboratory study. METHODS: Sixty adult rats underwent bilateral transection of their knee medial collateral ligaments. Animals were divided into 2 drug groups and treated 5 d/wk with celecoxib (5 mg/kg) mixed in a vehicle solution (NSAID group) or vehicle alone (VEH group). One to 3 hours after drug administration, all animals were treated with unilateral active low-intensity pulsed ultrasound and contralateral inactive low-intensity pulsed ultrasound. Equal numbers of animals from each drug group were mechanically tested at 2 weeks (n = 14/group), 4 weeks (n = 8/group), and 12 weeks (n = 8/group) after injury. RESULTS: Ultrasound and drug intervention did not interact to influence ligament mechanical properties at any time point. After 2 weeks of intervention, ligaments treated with active low-intensity pulsed ultrasound were 34.2% stronger, 27.0% stiffer, and could absorb 54.4% more energy before failure than could ligaments treated with inactive low-intensity pulsed ultrasound, whereas ligaments from the NSAID group could absorb 33.3% less energy than could ligaments from the VEH group. There were no ultrasound or drug effects after 4 and 12 weeks of intervention. CONCLUSIONS: Low-intensity pulsed ultrasound accelerated but did not improve ligament healing, whereas the nonsteroidal anti-inflammatory drug delayed but did not impair healing. When used in combination, the beneficial low-intensity pulsed ultrasound effect was cancelled by the detrimental nonsteroidal anti-inflammatory drug effect. CLINICAL RELEVANCE: Low-intensity pulsed ultrasound after ligament injury may facilitate earlier return to activity, whereas non-steroidal anti-inflammatory drugs may elevate early reinjury risk.

Animals↗
PubMed2006

Stress fractures: pathophysiology, epidemiology, and risk factors.

A stress fracture represents the inability of the skeleton to withstand repetitive bouts of mechanical loading, which results in structural fatigue and resultant signs and symptoms of localized pain and tenderness. To prevent stress fractures, an appreciation of their risk factors is required. These are typically grouped into extrinsic and intrinsic risk factors. Extrinsic risk factors for stress fractures are those in the environment or external to the individual, including the type of activity and factors involving training, equipment, and the environment. Intrinsic risk factors for stress fractures refer to characteristics within the individual, including skeletal, muscle, joint, and biomechanical factors, as well as physical fitness and gender. This article discusses these extrinsic and intrinsic risk factors, as well as the pathophysiology and epidemiology of stress fractures.

Female↗
PubMed2006

Preliminary evaluation of a load-bearing BMP-2 carrier for segmental defect regeneration.

Large segmental defects in bones can result from tumor removal, massive trauma, congenital malformation, or non-union fractures. Such defects often are difficult to manage and require multiple-phase surgery to achieve adequate union and function. In this study, we propose a novel design of bone morphogenetic protein 2 (BMP-2) carrier for tissue engineering of segmental defect regeneration. The tube-shaped BMP-2 carrier was fabrication from a poly(propylene fumarate)/tricalcium phosphate (PPF/TCP) composite via casting technique developed in our laboratory. An in vitro evaluation showed that the compressive strength of the carrier decreased about 48% in 12 weeks while maintained a pH in the 6.8-7.4 range. In vivo study was conducted by implanting carriers loaded with 10 microg of BMP-2 in 5 mm rat femur gap model for 15 weeks. X-ray evidence of bridging was first found in the BMP group at 3 weeks. Bridging in all animals (N = 4) in the BMP group was found at 9 weeks. No x-ray evidence of bridging was found in the No BMP group (N = 3). pQCT analysis indicated that the bone mineral density of the callus in the BMP group has reached the level of native femur at 15 weeks after implantation, while the callus in the No BMP group has a bone mineral density at a lower level of 84% to the native femur. Histology analysis shows that a normal fatty bone marrow was restored and mineralized callus formed and bridged the segmental defect.

Animals↗
PubMed2006

Ultrasound produced by a conventional therapeutic ultrasound unit accelerates fracture repair.

BACKGROUND AND PURPOSE: A recent novel application of ultrasound therapy is the treatment of bone fractures. The aim of this study was to investigate the effect on fracture repair of ultrasound produced by a conventional therapeutic ultrasound unit as used by physical therapists. SUBJECTS AND METHODS: Bilateral midshaft femur fractures were created in 30 adult male Long-Evans rats. Ultrasound therapy was commenced on the first day after fracture and introduced 5 days a week for 20 minutes a day. Each animal was treated unilaterally with active ultrasound and contralaterally with inactive ultrasound. Active ultrasound involved a 2-millisecond burst of 1.0-MHz sine waves repeating at 100 Hz. The spatially averaged, temporally averaged intensity was set at 0.1 W/cm2. Animals were killed at 25 and 40 days after fracture induction, and the fractures were assessed for bone mass and strength. RESULTS: There were no differences between fractures treated with active ultrasound and fractures treated with inactive ultrasound at 25 days. However, at 40 days, active ultrasound-treated fractures had 16.9% greater bone mineral content at the fracture site than inactive ultrasound-treated fractures. This change resulted in a 25.8% increase in bone size, as opposed to an increase in bone density, and contributed to active ultrasound-treated fractures having 81.3% greater mechanical strength than inactive ultrasound-treated fractures. DISCUSSION AND CONCLUSION: These data indicate that ultrasound produced by a conventional therapeutic ultrasound unit as traditionally used by physical therapists may be used to facilitate fracture repair. However, careful interpretation of this controlled laboratory study is warranted until its findings are confirmed by clinical trials.

Animals↗
PubMed2005

Knee ligament mechanical properties are not influenced by estrogen or its receptors.

Women are at greater risk of tearing their knee anterior cruciate ligament (ACL) than men participating in similar athletic activities. There is currently no conclusive explanation for this disparity; however, as ACL injuries in women have been linked with estrogen fluctuations during the menstrual cycle, one hypothesis is that estrogen has a direct detrimental effect on knee ligament mechanical properties. This study investigated the influence of estrogen and its receptors (ER alpha and ER beta) on knee ligament mechanical properties. This was achieved by testing the viscoelastic and tensile mechanical properties of knee medial collateral ligaments (MCL) and ACLs from: 1) male Sprague-Dawley rats treated with either estrogen (17alpha-ethynylestradiol; 0.03 mg/kg) or an ER alpha-specific agonist (propyl pyrazole triol; 2 mg/kg), and 2) female mice with a null mutation of the gene encoding for ER beta. Estrogen treatment had no significant effects on the viscoelastic or tensile mechanical properties of the rat MCL or ACL. Similarly, pharmacological stimulation of ER alpha using a selective agonist in rats and genetic modulation of ER beta by null mutation of its gene in mice did not influence MCL or ACL properties. These data indicate that estrogen does not have a major direct effect on ligament mechanical properties. Energies for the prevention of the disproportionately high rate of knee ligament injuries in women may be better spent focusing on more established and modifiable risk factors, such as abnormalities in neuromuscular control about the knee.

Animals↗
PubMed2005

Neural regulation of bone and the skeletal effects of serotonin (5-hydroxytryptamine).

There is increasing evidence for a contribution of the neural system to the regulation of bone metabolism. The skeleton is richly innervated by both sympathetic and sensory neurons. While these nerves serve sensory and vascular functions, they are also being found to influence bone cell activities. The most convincing evidence for this has been provided by studies into the skeletal effects of the hormone leptin, which has been shown to centrally regulate bone mass, and through studies into the skeletal effects of hypothalamic neuropeptide Y2 and Y4 receptors. This paper discusses recent evidence for the neural regulation of bone metabolism and, in particular, the potential role of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Recent studies have demonstrated the presence of functional pathways in bone for both responding to and regulating the uptake of 5-HT. This is of high clinical relevance given the role of the serotonergic system in affective disorders, and the wide use of pharmacological agents that target the 5-HT system to manage these disorders. Initial data suggest that exposure to these agents at different stages during the lifespan may have significant effects on the skeleton.

Bone and Bones↗
PubMed2005

A comparison of mechanical properties derived from multiple skeletal sites in mice.

Laboratory mice provide a versatile experimental model for studies of skeletal biomechanics. In order to determine the strength of the mouse skeleton, mechanical testing has been performed on a variety of bones using several procedures. Because of differences in testing methods, the data from previous studies are not comparable. The purpose of this study was to determine which long bone provides the values closest to the published material properties of bone, while also providing reliable and reproducible results. To do this, the femur, humerus, third metatarsal, radius, and tibia of both the low bone mass C57BL/6H (B6) and high bone mass C3H/HeJ (C3H) mice were mechanically tested under three-point bending. The biomechanical tests showed significant differences between the bones and between mouse strains for the five bones tested (p < 0.05). Computational models of the femur, metatarsal, and radius were developed to visualize the types of measurement error inherent in the three-point bending tests. The models demonstrated that measurement error arose from local deformation at the loading point, shear deformation and ring-type deformation of the cylindrical cross-section. Increasing the aspect ratio (bone length/width) improved the measurement of Young's modulus of the bone for both mouse strains (p < 0.01). Bones with the highest aspect ratio and largest cortical thickness to radius ratio were better for bending tests since less measurement error was observed in the computational models. Of the bones tested, the radius was preferred for mechanical testing because of its high aspect ratio, minimal measurement error, and low variability.

Animals↗
PubMed2005

Cellular accommodation and the response of bone to mechanical loading.

Several mathematical rules by which bone adapts to mechanical loading have been proposed. Previous work focused mainly on negative feedback models, e.g., bone adapts to increased loading after a minimum strain effective (MES) threshold has been reached. The MES algorithm has numerous caveats, so we propose a different model, according to which bone adapts to changes in its mechanical environment based on the principle of cellular accommodation. With the new algorithm we presume that strain history is integrated into cellular memory so that the reference state for adaptation is constantly changing. To test this algorithm, an experiment was performed in which the ulnae of Sprague-Dawley rats were loaded in axial compression. The animals received loading for 15 weeks with progressively decreasing loads, increasing loads, or a constant load. The results showed the largest increases in geometry in the decreasing load group, followed by the constant load group. Bone formation rates (BFRs) were significantly greater in the decreasing load group during the first 2 weeks of the study as compared to all other groups (P<0.05). After the first few weeks of mechanical loading, the BFR in the loaded ulnae returned to the values of the nonloaded ulnae. These experimental results closely fit the predicted results of the cellular accommodation algorithm. After the initial weeks of loading, bone stopped responding so the degree of adaptation was proportional to the initial peak load magnitude.

Adaptation, Physiological↗
PubMed2005

Cyclo-oxygenase-2 inhibitors : beneficial or detrimental for athletes with acute musculoskeletal injuries?

The major goal of clinicians when treating acute musculoskeletal injuries is to return athletes to their pre-injury level of function, ideally in the shortest time possible and without compromising tissue-level healing. In this regard, a commonly used intervention is the taking of NSAIDs. These are used to limit the amount and duration of inflammation, and to control pain. While NSAIDs have become synonymous with the management of acute musculoskeletal injuries, their efficacy has yet to be proven. This is of particular concern in view of recent research investigating the latest class of NSAIDs - selective cyclo-oxygenase-2 inhibitors (COXIBs). COXIBs were developed to reduce the adverse gastrointestinal (GI) effects of traditional NSAIDs. While they have beneficial anti-inflammatory and analgesic properties, and appear to facilitate earlier return to function following acute injury, the effect of COXIBs on tissue-level healing is currently unknown. In experimental animal models of acute injury, COXIBs have been shown to be detrimental to tissue-level repair. Specifically, they have been shown to impair mechanical strength return following acute injury to bone, ligament and tendon. Clinically, this may have implications for ongoing morbidity and future injury susceptibility. However, the current animal studies have limited translation to the clinical setting, particularly because of significant limitations relating to drug use and dosage in these studies. There is currently no randomised, controlled trial evidence of the tissue-level effects of COXIBs on acute musculoskeletal injuries. In addition to questions relating to the effect of COXIBs on tissue-level healing, further questions regarding the use of these agents have been raised given a recent link being shown between one COXIB (rofecoxib) and an increased risk for adverse cardiovascular events. Whether this finding is related to the individual properties of rofecoxib or is a class phenomenon is the subject of ongoing investigation. However, in light of the potential risks associated with using COXIBs, an acceptable and possibly safer alternative in the management of acute musculoskeletal injuries may be to use traditional NSAIDs. Traditional NSAIDs do carry the potential for greater adverse GI effects and their clinical effects on tissue-level healing remain relatively unknown. However, they do not appear to be associated with adverse cardiovascular effects, and they are effective pain relievers and cheaper alternatives.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Bone adaptation to a mechanical loading program significantly increases skeletal fatigue resistance.

UNLABELLED: Using a mechanical loading program to induce bone adaptation, we found that small (<2-fold) changes in the structural properties of the rat ulna increased its fatigue resistance >100-fold. This indicates that a moderate exercise program may be an effective preventative strategy for stress fractures. INTRODUCTION: There are currently limited preventative strategies for stress fractures. Because stress fracture risk is directly influenced by skeletal properties, it has been hypothesized that modification of these properties using a mechanical loading program may positively influence risk. The aim of this study was to investigate whether the bone changes associated with a mechanical loading program can enhance skeletal fatigue resistance. MATERIALS AND METHODS: Site-specific mechanical loading was performed on one forearm of adult female Sprague-Dawley rats using the axial compression loading model. Loading was performed 3 days/week for 5 consecutive weeks to induce adaptation. The loaded and nonloaded ulnas in each animal were removed after the loading program, and their material and structural properties were determined. The ulna pairs were subsequently loaded until fatigue failure at the same constant peak axial load. RESULTS: Mechanical loading induced consistent and predictable changes in the structural properties of loaded ulnas, with the largest change being a nearly 2-fold increase in midshaft minimum second moment of area (I(MIN)). The mechanical-loading induced bone changes resulted in a >100-fold increase in fatigue resistance in loaded ulnas, with resistance being exponentially related to the structural properties of the ulna. CONCLUSIONS: This study found that by enhancing the structural properties of a bone through a mechanical loading program, its fatigue resistance could be significantly improved. This indicates that an exercise program aimed at modifying bone structure may be used as a possible prevention strategy for stress fractures.

Animals↗
PubMed2004

Mechanotransduction in bone does not require a functional cyclooxygenase-2 (COX-2) gene.

UNLABELLED: COX-2 is a key enzyme involved in the response of bone to loading. However, using mice with a null mutation of the COX-2 gene, we found that a functional COX-2 gene is not required for mechanotransduction. This paradoxical finding may have resulted, in part, from mechanically induced COX-1 activity. INTRODUCTION: Cyclooxygenase-2 (COX-2) is an important mediator in the response of bone to mechanical loading, with pharmacological inhibition of COX-2 effectively eliminating or reducing mechanically induced bone formation. In this study, we further investigated the role of COX-2 in skeletal mechanotransduction using a genetic approach. The aim was to compare the skeletal responsiveness of COX-2 homozygous mutant (COX-2(-/-)) and wildtype control (COX-2(+/+)) mice to investigate whether a functional COX-2 gene is necessary for mechanotransduction. MATERIALS AND METHODS: Adult female COX-2(+/+) and COX-2(-/-) mice on a C57BL/6x129/ola background were studied using the ulna axial loading model. The response to 2 days of loading for 120 cycles/day at 2 Hz was measured histomorphometrically. Phenotypic characterization of the femurs in these mice was also performed. In a separate group of animals, the expression of the remaining COX isozyme, COX-1, was assessed using real-time RT-PCR 4 h after one bout of 120 loading cycles. RESULTS: Null mutation of the COX-2 gene resulted in a consistent femoral phenotype of reduced bone mass, altered architecture, and inferior mechanical properties. Many of these differences were nullified after adjustment for body weight. Nevertheless, body weight-corrected values showed a consistent trend of reduced mechanical properties in COX-2(-/-) mice. Genotype did not influence the response to mechanical loading, with no histomorphometric differences being found between COX-2(+/+) and COX-2(-/-) mice. Real-time RT-PCR showed COX-2(-/-) mice to express significantly greater COX-1 expression in loaded ulnas than in loaded ulnas in COX-2(+/+) mice. There were no differences in COX-1 expression in nonloaded ulnas. CONCLUSIONS: A functional COX-2 gene was not found to be required for skeletal mechanotransduction. This is in contrast to previous pharmacological studies showing that COX-2 is critical to the response of bone to loading. Investigating a potential reason for the absence of a genotype difference in this study, we found that mice with a null mutation in the COX-2 gene possess inductive skeletal COX-1 expression.

Animals↗
PubMed2004

Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth.

Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI. In both models, 5-HTT inhibition had significant detrimental effects on bone mineral accrual. 5-HTT null mutant mice had a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties, whereas bone mineral accrual was impaired in growing mice treated with a SSRI. These phenotypes resulted from a reduction in bone formation without an increase in bone resorption and were not influenced by effects on skeletal mechanosensitivity or serum biochemistries. These findings indicate a role for the 5-HTT in the regulation of bone accrual in the growing skeleton and point to a need for further research into the prescription of SSRIs to children and adolescents.

Animals↗