Adaptive Response Of Bone Research Articles

Identification of genetic loci that regulate bone adaptive response to mechanical loading in C57BL/6J and C3H/HeJ mice intercross

Strain-dependent differences in bone adaptive responses to loading among inbred mouse strains suggest that genetic background contributes significantly to adaptation to exercise. To explore the genetic regulation of response to loading, we performed a genome-wide search for linkage in a cross between two strains, a good responder, C57BL6/J (B6), and a poor responder, C3H/HeJ (C3H). Using a four-point bending model, the right tibia was loaded by applying 9 N force for 36 cycles for 12 days in 10-week-old female B6×C3H F2 mice. Changes in bone density (BMD) and bone size were evaluated in vivo by pQCT. Measurements from non-loaded left tibia were used as an internal control to calculate loading-induced percent increase in BMD and bone size, thus excluding the possibility of identifying background QTL(s) due to natural allelic variation in mapping strains. A genome-wide scan was performed using 111 microsatellite markers in DNA samples collected from 329 F2 mice. Heritability of bone adaptive response to loading was between 70 and 80%. The mean increase, expressed as percent of unloaded tibia, was 5% for BMD, 9% for periosteal circumference (PC), and 14% for cortical thickness in F2 mice ( n = 329). All these phenotypes showed normal distributions. Absence of significant correlation between BMD response to four-point bending and body weight or bone size suggested that the bone adaptive response was independent of bone size. Interval mapping revealed that BMD response to four-point bending was influenced by three significant loci on Chrs 1 (log-of-odds ratio score (LOD) 3.4, 91.8 cM), 3 (LOD 3.6, 50.3 cM), and 8 (LOD 4.2, 60.1 cM) and one suggestive QTL on Chr 9 (LOD 2.5, 33.9 cM). Loading-induced increases in PC and Cth were influenced by four significant loci on Chrs 8 (LOD 3.0, 68.9 cM), 9 (LOD 3.0, 13.1 cM), 17 (LOD 3.0, 39.3 cM), and 18 (LOD 3.0, 0 cM) and two suggestive loci on Chr 9 (LOD 2.2, 24 cM) and 11 (LOD 2.1, 69.9 cM). Pairwise analysis showed the presence of several significant and suggestive interactions between loci on Chrs 1, 3, 8, and 13 for BMD trait. This is the first study that provides evidence for the presence of multiple genetic loci regulating bone anabolic responses to loading in the B6×C3H intercross. Knowledge of the genes underlying these loci could provide novel approaches to improve skeletal mass.

Release of nitric oxide, but not prostaglandin E2, by bone cells depends on fluid flow frequency

Loading frequency is an important parameter for the stimulation of bone formation in vivo. It is still unclear how the information of external loading characteristics is conveyed to osteoblasts and osteoclasts. Osteocytes are thought to detect mechanical loads by sensing fluid flow through the lacuno-canalicular network within bone and to translate this information into chemical signals. The signaling molecules nitric oxide (NO) and prostaglandin E2 (PGE2) are known to play important roles in the adaptive response of bone to mechanical loads. We have investigated the effects of fluid flow frequency on the production of PGE2 and NO in bone cells in vitro. Pulsatile fluid flow with different frequencies stimulated the release of NO by MC3T3-E1 osteoblasts in a dose-dependent manner. In contrast, PGE2 production was enhanced consistently by all fluid flow regimes, independent of flow frequency. This implies that the NO response may play a role in mediating the differential effects of the various loading patterns on bone.

Breaking the rules for bone adaptation to mechanical loading

The ability of bone to respond to mechanical stimuli has been known for over a century; however, it has only been in the past several decades that great gains have been made in terms of understanding the factors that influence this response. For instance, we now know that 1 ) bone preferentially

Regional Bone Mineral Density of the Tibia in Female Soldiers Following 16-Weeks of Recruit Training

The bone adaptation response to exercise is specific to the site being loaded, and may differ between regions of trabecular and cortical bone. It has been suggested that strenuous physical training may result in decreased bone mineral density (BMD) at regions susceptible to stress fracture. Additionally, individuals may respond uniquely to comparable exercise programs. PURPOSE: 1) To determine if regional BMD of the tibia decreases following 16 weeks of recruit training, and 2) to assess whether a change in tibial BMD is related to onset of lower extremity stress fracture. METHODS: 105 women (18.9 ± 0.5 yr) underwent DXA scanning before and after a 16-wk recruit training program in the Israeli Defense Forces. 57 women participated in a physically rigorous combat training program and did not sustain a stress fracture (no stress fracture), 10 participated in rigorous training and were diagnosed with a stress fracture (stress fracture), and 38 completed an academic program with light physical activity requirements (control). BMD was assessed at 5 regions of interest (ROI) at points 4, 33, 50, 66, and 95% from the distal end plate of the tibia. The 4 and 95% regions reflect predominantly trabecular bone; the 33, 50, and 66% sites reflect cortical bone. The 33 and 95% sites are the most frequent site of stress fracture. A total tibial BMD value was calculated as the mean of the five ROIs. Data were analyzed using a repeated measures ANOVA and Tukey post hoc testing. RESULTS: Stress fracture incidence was 14.9% in the combat training group, whereas there were no stress fractures in the control group. The following table presents tibial BMD (g/cm2) compared across groups for each ROI (mean±SD):Table 1Only the control group exhibited changes in tibial BMD over the study period, with increases evident at the 33% and 95% regions. CONCLUSION: Sixteen weeks of strenuous training did not result in decreased tibial BMD, whereas light physical training over the same period increased BMD at two regions, and resulted in a small but significant overall increase in tibial density.

Estimation of bone permeability using accurate microstructural measurements

While interstitial fluid flow is necessary for the viability of osteocytes, it is also believed to play a role in bone's mechanosensory system by shearing bone cell membranes or causing cytoskeleton deformation and thus activating biochemical responses that lead to the process of bone adaptation. However, the fluid flow properties that regulate bone's adaptive response are poorly understood. In this paper, we present an analytical approach to determine the degree of anisotropy of the permeability of the lacunar–canalicular porosity in bone. First, we estimate the total number of canaliculi emanating from each osteocyte lacuna based on published measurements from parallel-fibered shaft bones of several species (chick, rabbit, bovine, horse, dog, and human). Next, we determine the local three-dimensional permeability of the lacunar–canalicular porosity for these species using recent microstructural measurements and adapting a previously developed model. Results demonstrated that the number of canaliculi per osteocyte lacuna ranged from 41 for human to 115 for horse. Permeability coefficients were found to be different in three local principal directions, indicating local orthotropic symmetry of bone permeability in parallel-fibered cortical bone for all species examined. For the range of parameters investigated, the local lacunar–canalicular permeability varied more than three orders of magnitude, with the osteocyte lacunar shape and size along with the 3-D canalicular distribution determining the degree of anisotropy of the local permeability. This two-step theoretical approach to determine the degree of anisotropy of the permeability of the lacunar–canalicular porosity will be useful for accurate quantification of interstitial fluid movement in bone.

COX-2 is necessary for venous ligation-mediated bone adaptation in mice

In osteoblasts, cyclooxygenase 2 (COX-2) is the major isozyme responsible for production of prostaglandins. Prostaglandins are local mediators of bone resorption and formation and are known to be involved in bone's adaptive response to fluid shear stress (FSS). We have previously described a model of trabecular bone loss in hindlimb-suspended mice and rats and demonstrated partial protection from osteopenia by ligation of the femoral vein. The increased FSS resulting from this ligation drove bone adaptation in the absence of mechanical loading. In this study, we investigated the role of COX-2 in this adaptive response to FSS by use of COX-2 knockout mice. COX-2 knockout (“KO”), COX-2 heterozygote (“HET”), and COX-2 wild-type (“WT”) animals all lost comparable amounts of trabecular bone from sham-operated limbs as a result of suspension. In WT mice, loss of trabecular BMD in the venous-ligated limb was significantly less than that of the sham-operated limb; this effect, however, was not seen in KO or HET mice. Percentage gain in femoral periosteal circumference was greater in the ligated limb than the sham-operated limb for WT mice. KO and HET mice already possess femora of larger periosteal circumference than their WT littermates and ligation in these bones did not result in an increase in perimeter relative to sham. Histomorphometry on embedded bones revealed thinner cortices and less mineralizing perimeter in KO femora than controls. In conclusion, this is the first in vivo study to show that fluid-flow-mediated bone adaptation, independent of mechanical strain, is COX-2 dependent.

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.

The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta.

Postmenopausal osteoporosis represents a failure of the response by which bone cells adapt bone mass and architecture to be sufficiently strong to withstand loading without fracture. To address why this failure should be associated with oestrogen withdrawal, we investigated the ulna's adaptive response to mechanical loading in adult female mice lacking oestrogen receptor-alpha (ERalpha(-/-)), those lacking oestrogen receptor-beta (ERbeta(-/-)) and their wild-type littermates. In wild-type mice, short periods of physiologic cyclic compressive loading of the ulna in vivo over a 2-week period stimulates new bone formation. In ERalpha(-/-) and ERbeta(-/-) mice this osteogenic response was respectively threefold and twofold less (P<0.05). In vitro, primary cultures of osteoblast-like cells derived from these mice were subjected to a single short period of mechanical strain. Twenty-four hours after strain the number of wild-type cells was 61+/-25% higher than in unstrained controls (P<0.05), whereas in ERalpha(-/-) cells there was no strain-related increase in cell number. However, the strain-related response of ERalpha(-/-) cells could be partially rescued by transfection with functional human ERalpha (P<0.05). ERbeta(-/-) cells showed a 125+/-40% increase in cell number following strain. This was significantly greater than in wild types (P<0.05).These data support previous findings that functional ERalpha is required for the full osteogenic response to mechanical loading and particularly the stage of this response, which involves an increase in osteoblast number. ERbeta appears to depress the ERalpha-mediated strain-related increase in osteoblast number in vitro, but in female transgenic mice in vivo the constitutive absence of either ERalpha or ERbeta appears to diminish the osteogenic response to loading.

Bone biomechanical properties in LRP5 mutant mice

The mutation responsible for the high bone mass (HBM) phenotype has been postulated to act through the adaptive response of bone to mechanical load resulting in denser and stronger skeletons in humans and animals. The bone phenotype of members of a HBM family is characterized by normally shaped bones that are exceptionally dense, particularly at load bearing sites [Cancer Res. 59 (1999) 1572]. The high bone mass (HBM) mutation was identified as a glycine to valine substitution at amino acid residue 171 in the gene coding for low-density lipoprotein receptor-related protein 5 (LRP5) [Bone Miner. Res. 16(4) (2001) 758]. Thus, efforts have focused on the examination of the role of LRP5 and the G171V mutation in bone mechanotransduction responses [J. Bone Miner. Res 18 (2002) 960]. Transgenic mice expressing the human G171V mutation have been shown to have skeletal phenotypes remarkably similar to those seen in affected individuals. In this study, we have identified differences in biomechanical (structural and apparent material) properties, bone mass/ash, and bone stiffness of cortical and cancellous bone driven by the G171V mutation in LRP5. As in humans, the LRP5 G171V plays an important role in regulating bone structural phenotypes in mice. These bone phenotypes include greater structural and apparent material properties in HBM HET as compared to non-transgenic littermates (NTG) mice. Body size and weight in HBM HET were similar to that in NTG control mice. However, the LRP5 G171V mutation in HET mice results in a skeleton that has greater structural (femoral shaft, femoral neck, tibiae, vertebral body) and apparent material (vertebral body) strength, percent bone ash weight (ulnae), and tibial stiffness. Despite similar body weight to NTG mice, the denser and stiffer bones in G171V mice may represent greater bone formation sensitivity to normal mechanical stimuli resulting in an overadaptation of skeleton to weight-related forces.

In vivo micro-CT-based FE models of guinea pigs with titanium implants: an STL-based approach

This paper focuses on methods for generating a finite element model (FEM) based on in vivo microfocus computed tomography (μCT) images of guinea pig tibiae with a titanium percutaneous implant. A standard triangulated language (STL)-based approach was developed. Bone geometry was derived based on a pre-operative, metal artefact-free STL representation. Correct positioning of the implant with respect to the bone was implemented in a matching procedure of the post-operative bone representation onto the pre-operative representation. After further adaptation of the STL triangulation, it was converted into a tetrahedral FE mesh. To build FE models based on μCT-derived STL representations is a more efficient and accurate procedure than by implementing a CAD-based approach. The new STL-based procedure increases the usefulness of FE models as an interpretation tool for in vivo μCT images. In future work, these in vivo μCT-based finite element models will be used to implement algorithms that simulate adaptive bone response to controlled mechanical stimuli.

Gender differences in bone turnover in 2‐year‐old Thoroughbreds

Injuries to the skeleton are a major cause of morbidity and mortality in racehorses and age, gender and season have all been shown to influence risk of injury. To use biochemical markers of bone cell activity to establish to whether cellular processes in bone underlie these described effects. Blood samples were collected monthly from 2-year-old horses in race training between November 1998 and September 1999. Mean age at the start of the study was 20 months (range 18-23 months), with no significant difference in average age between colts (n = 84) and fillies (n = 63). Three markers were measured; osteocalcin (OC, bone formation), the carboxyterminal cross-linked telopeptide of type I collagen (ICTP, bone resorption) and the carboxyterminal propeptide of type I collagen (PICP), which is less 'bone-specific' than the other 2 markers. Colts had, on average, 3.62 ng/ml higher OC concentrations (P = 0.044) and 0.68 mg/l higher ICTP concentrations (P = 0.01) than fillies. The effect of gender was not statistically significant for PICP. However, in May, PICP concentrations were on average 157 mg/l higher in fillies than colts. There was no effect of age or season on marker concentrations. This study has shown that there are gender differences in bone turnover markers in 2-year-old Thoroughbreds; however, age, within the limited range studied, did not have a significant effect on bone cell activity. Lower bone marker concentrations may reflect smaller bone size and/or earlier skeletal maturation in fillies. An increase in concentrations of PICP in fillies in spring and early summer may relect an influence of sex hormones on collagen turnover. Gender differences in bone cell activity in 2-year-old colts and fillies may influence bone's adaptive responses to training and risk of injury.

Individualised, micro CT-based finite element modelling as a tool for biomechanical analysis related to tissue engineering of bone

Load-bearing tissues, like bone, can be replaced by engineered tissues or tissue constructs. For the success of this treatment, a profound understanding is needed of the mechanical properties of both the native bone tissue and the construct. Also, the interaction between mechanical loading and bone regeneration and adaptation should be well understood. This paper demonstrates that microfocus computer tomography (μCT) based finite element modelling (FEM) can have an important contribution to the field of functional bone engineering as a biomechanical analysis tool to quantify the stress and strain state in native bone tissue and in tissue constructs. Its value is illustrated by two cases: (1) in vivo μCT-based FEM for the analysis of peri-implant bone adaptation and (2) design of biomechanically optimised bone scaffolds. The first case involves a combined animal experimental and numerical study, in which the peri-implant bone adaptive response is monitored by means of in vivo μCT scanning. In the second case μCT-based finite element models were created of native trabecular bone and bone scaffolds and a mechanical analysis of both structures was performed. Procedures to optimise the mechanical properties of bone scaffolds, in relation to those of native trabecular bone are discussed.

Fluid pressure gradients, arising from oscillations in intramedullary pressure, is correlated with the formation of bone and inhibition of intracortical porosity

Fluid flow that arises from the functional loading of bone tissue has been proposed to be a critical regulator of skeletal mass and morphology. To test this hypothesis, the bone adaptive response to a physiological fluid stimulus, driven by low magnitude, high frequency oscillations of intramedullary pressure (ImP), were examined, in which fluid pressures were achieved without deforming the bone tissue. The ulnae of adult turkeys were functionally isolated via transverse epiphyseal osteotomies, and the adaptive response to four weeks of disuse ( n=5) was compared to disuse plus 10 min per day of a physiological sinusoidal fluid pressure signal (60 mmHg, 20 Hz). Disuse alone resulted in significant bone loss (5.7±1.9%, p⩽0.05), achieved by thinning the cortex via endosteal resorption and an increase in intracortical porosity. By also subjecting bone to oscillatory fluid flow, a significant increase in bone mass at the mid-diaphysis (18.3±7.6%, p<0.05), was achieved by both periosteal and endosteal new bone formation. The spatial distribution of the transcortical fluid pressure gradients (∇ P r ), a parameter closely related to fluid velocity and fluid shear stress, was quantified in 12 equal sectors across a section at the mid-diaphyses. A strong correlation was found between the ∇ P r and total new bone formation ( r=0.75, p=0.01); and an inverse correlation ( r=−0.75, p=0.01) observed between ∇ P r and the area of increased intracortical porosity, indicating that fluid flow signals were necessary to maintain bone mass and/or inhibit bone loss against the challenge of disuse. By generating this fluid flow in the absence of matrix strain, these data suggest that anabolic fluid movement plays a regulatory role in the modeling and remodeling process. While ImP increases uniformly in the marrow cavity, the distinct parameters of fluid flow vary substantially due to the geometry and ultrastructure of bone, which ultimately defines the spatial non-uniformity of the adaptive process.

Suppression of Prostaglandin Synthesis with NS-398 Has Different Effects on Endocortical and Periosteal Bone Formation Induced by Mechanical Loading

Prostaglandins mediate adaptive bone formation induced by mechanical loading. Inhibition of cyclooxygenase-2 (COX-2) with NS-398 effectively blocks loading-induced osteogenesis on the endocortical bone surface of the tibia. In this study, we compared the effects of selective inhibition of COX-2 with NS-398 on mechanically induced osteogenesis at the endocortical surface (tibia) with that on the periosteal surface (ulna). We further tested the effect of NS-398 administered at different times before (3 hrs or 30 min) or after (30 min) mechanical loading. Mechanical loading induced lamellar bone formation on the endocortical surface of the tibia and the periosteal surface of the ulna. Oral administration of either indomethacin or NS-398 3 hrs before loading significantly decreased loading-induced bone formation rate (BFR) and mineralizing surface (MS/BS), but not mineral apposition rate (MAR), at the endocortical surface of the tibia and the periosteal surface of the ulna. NS-398 reduced loading-induced MS/BS by 96% on the endocortical surface of the tibia, but only by 37% on the periosteal surface of the ulna (significantly different from endocortical, P <0.05). Indomethacin reduced MS/BS and BFR to a lesser extent than NS-398 and did not have different effects on the periosteal and endocortical surfaces. These data suggest that the endocortical bone adaptive response to mechanical loading is more dependent upon COX-2 activity than is the periosteal bone response. Intraperitoneal injection of NS-398 3 hrs before loading suppressed load-induced bone formation rate at the endocortical surface of the tibia significantly more (27%) than when administered 30 min before loading. When NS-398 was given 30 min after loading, bone formation was not significantly suppressed. These data suggest that a primary cellular mechanism of bone formation following brief bouts of mechanical loading involves release of prostaglandins from cells at the time mechanical loading is applied, rather than new prostaglandin synthesis associated with a mechanically induced COX-2 expression.

A time course of bone response to jump exercise in C57BL/6J mice

Exercise, by way of mechanical loading, provides a physiological stimulus to which bone tissue adapts by increased bone formation. The mechanical stimulus due to physical activity depends on both the magnitude and the duration of the exercise. Earlier studies have demonstrated that jump training for 4 weeks produces a significant bone formation response in C57BL/6J mice. An early time point with significant increase in bone formation response would be helpful in: (1) designing genetic quantitative trait loci (QTL) studies to investigate genes regulating the bone adaptive response to mechanical stimulus; and (2) mechanistic studies to investigate early stimulus to bone tissue. Consequently, we investigated the bone structural response after 2, 3, and 4 weeks of exercise with a loading cycle of ten jumps a day. We used biochemical markers and peripheral quantitative computed tomography (pQCT) of excised femur to measure bone density, bone mineral content (BMC), and area. Four-week-old mice were separated into control ( n = 6) and jump groups ( n = 6), and the latter groups of mice were subjected to jump exercise of 2-week, 3-week, and 4-week duration. Data (pQCT) from a mid-diaphyseal slice were used to compare bone formation parameters between exercise and control groups, and between different time points. There was no statistically significant change in bone response after 2 weeks of jump exercise as compared with the age-matched controls. After 3 weeks of jump exercise, the periosteal circumference, which is the most efficient means of measuring adaptation to exercise, was increased by 3% ( P < 0.05), and total and cortical area were increased by 6% ( P < 0.05) and 11% ( P < 0.01), respectively. Total bone mineral density (BMD) increased by 11% ( P < 0.01). The biggest changes were observed in cortical and total BMC, with the increase in total BMC being 12% ( P < 0.01). Interestingly, the increase in BMC was observed throughout the length of the femur and was not confined to the mid-diaphysis. Consistent with earlier studies, mid-femur bone mass and area remained significantly elevated in the 4-week exercise group when compared with the control group of mice. The levels of the biochemical markers osteocalcin, skeletal alkaline phosphatase, and C-telopeptide were not significantly different between the exercise and control groups, indicating the absence of any systemic response due to the exercise. We conclude that a shorter exercise regimen, of 3 weeks, induced a bone response that was greater than or equal to that of 4 weeks of jump exercise reported earlier.

Bone biomechanical properties in prostaglandin EP 1 and EP 2 knockout mice

Prostaglandins play an important role in regulating the bone adaptation response to mechanical stimuli. Prostaglandin E2 (PGE 2) is an effective modulator of bone metabolism. Administration of PGE 2 to rodents results in increased cancellous and cortical bone mass translating into enhanced mechanical strength. The PGE 2 influence on bone is mediated through four well-characterized receptors (EP 1, EP 2, EP 3, and EP 4). Although the PGE 2 pathways and mechanisms of action on cells involved in bone adaptation are still under investigation, it is now known that each receptor plays a unique role in regulating PGE 2-related bone cell function. The EP 1 subtype is coupled with Ca 2+ mobilization. The EP 2 subtype stimulates cyclic adenosine monophosphate (cAMP) formation. cAMP in turn is responsible for the early cellular signal that stimulates bone formation. This study compared physical and biomechanical properties of bone in EP 1 and EP 2 knockout mice to their corresponding wild-type controls. Ash weight was measured in the ulnae, and femurs and vertebral bodies were tested in three-point bending and compression, respectively. The results suggest: (a) EP 1 receptors have a minimal influence on skeletal strength or size in mice; and (b) EP 2 receptors have a major influence on the biomechanical properties of bone in mice. The absence of EP 2 receptors resulted in weak bone biomechanical strength properties in the EP 2 knockout model as compared with the corresponding wild-type control mice.

Differential Stimulation of Prostaglandin G/H Synthase-2 in Osteocytes and Other Osteogenic Cells by Pulsating Fluid Flow

Mechanical stress produces flow of fluid in the osteocytic lacunar–canalicular network, which is likely the physiological signal for the adaptive response of bone. We compared the induction of prostaglandin G/H synthase-2 (PGHS-2) by pulsating fluid flow (PFF) and serum in osteocytes, osteoblasts, and periosteal fibroblasts, isolated from 18-day-old fetal chicken calvariae. A serum-deprived mixed population of primarily osteocytes and osteoblasts responded to serum with a two- to threefold induction of PGHS-2 mRNA. Serum stimulated PGHS-2-derived PGE2 release from osteoblasts and osteocytes but not from periosteal fibroblasts as NS-398, a PGHS-2 blocker, inhibited PGE2 release from osteocytes and osteoblasts with 65%, but not that from periosteal fibroblasts. On the other hand PFF (0.7 Pa, 5 Hz) stimulated (3 fold) PGHS-2 mRNA only in OCY. The related PGE2 response could be completely inhibited by NS-398. We conclude that osteocytes have a higher intrinsic sensitivity for loading-derived fluid flow than osteoblasts or periosteal fibroblasts.

Perspectives on Bone Mechanical Properties and Adaptive Response to Mechanical Challenge

Abstract The bones of the human skeleton serve a mechanical function besides providing a reservoir for calcium and hematopoietic homeostasis. When mechanically challenged, they usually respond and adapt; failure to do so can result in fracture. The mechanical behavior of bone is determined by bone mass and its material properties and by its geometry and architecture. Therefore, in vivo noninvasive measurements of bone mass, geometry, and structure can predict bone strength and are usually employed as a useful—if not always reliable—way to estimate bone fragility, whereas direct bone biomechanical testing in vitro can provide detailed information about mechanical strength. Because bone strains are likely to be important regulators of bone mass and strength, exercise protocols designed to counteract the effects of osteoporosis should load the target bone with repeated high peak forces and high strain rates or high impacts on a long-term basis. Such a protocol creates varied strain distributions throughout the bone structure, producing short, repeated strains on the bone in directions to which it is unaccustomed. Exercise in this manner can maintain and perhaps increase bone mass and improve mechanical properties and neuromuscular competency, reducing skeletal fragility and the predisposition to falls.

Using functional loading to influence bone mass and architecture: objectives, mechanisms, and relationship with estrogen of the mechanically adaptive process in bone

There is increasing evidence that load-bearing is an important, if not the most important, functional influence on bone mass and architecture. Load-bearing most probably exerts its influence through the dynamic strains engendered in the bone tissue. Mechanically adaptive bone modeling and remodeling can be regarded as a homeostatic mechanism regulating functional bone strains at each location throughout the skeleton. Because most long bones are loaded in a certain amount of bending normal function, strains vary across the bones' cross-section. Both the longitudinal curvature and cross-sectional shape of a number of bones engender strains during functional loading rather than reduce them. Bone's adaptive response to load-bearing therefore results in functional strains which are neither uniform in distribution nor minimal in magnitude. Not all aspects of bone's strain environment are equally effective as influences on bone architecture. Unusual strain distributions, high strains, and high strain rates seem to be particularly osteogenic. The osteogenic response which follows exposure to such strains appears to saturate after only a few loading cycles. This is consistent with adaptive bone (re)modeling being sensitive to strain “errors,” which are not repeated frequently, rather than the repetitious strain cycles engendered during normal predominant activities. Exercise regimens designed to control bone architecture can usefully capitalize on this feature of the adaptive (re)modeling response. Each exercise session need not be prolonged but should include as many novel strain distributions as possible, preferably involving high peak strains and strain rates. To maintain any level of bone mass requires a continued, loading-related osteoregulatory stimulus. Exposure to appropriate load-bearing exercise needs therefore to be repeated, probably at daily or alternate-daily intervals. In short-term experiments in rat bones, estrogen amplifies the osteogenic response to a single period of loading. The features of postmenopausal bone loss are consistent with the etiology of the condition being primarily withdrawal of estrogen's contribution to bone's mechanically adaptive response.

Evidence for Remedial Medical Treatment of a Severe Knee Injury from the Fishergate Gilbertine Monastery in the City of York

During the analysis of a skeletal population from the Fishergate site in the City of York, an individual from the eastern part of the cemetery associated with the Gilbertine monastic foundation of St. Andrew revealed evidence of a chronic septic arthritis, secondary to a severe right knee twist-fracture, and bone adaptation in response to altered biomechanical loading. This disability had been the subject of remedial medical treatment with copper-alloy plates. Their presence, only the fourth such treatment thus far recorded from the mediaeval period, and the sole example applied to a lower limb, suggests that monastic houses, or those buried at these establishments, and specifically those associated with the Cistercians, had preferential access to medical specialists.