Sclerostin's role in bone's adaptive response to mechanical loading

Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis

The Contribution of Experimental <i>in vivo </i>Models to Understanding the Mechanisms of Adaptation to Mechanical Loading in Bone

Changing loading regimens by natural means such as exercise, with or without interference such as osteotomy, has provided useful information on the structure:function relationship in bone tissue. However, the greatest precision in defining those aspects of the overall strain environment that influence modeling and remodeling behavior has been achieved by relating quantified changes in bone architecture to quantified changes in bones’ strain environment produced by direct, controlled artificial bone loading.Jiri Heřt introduced the technique of artificial loading of bones in vivo with external devices in the 1960s using an electromechanical device to load rabbit tibiae through transfixing stainless steel pins. Quantifying natural bone strains during locomotion by attaching electrical resistance strain gauges to bone surfaces was introduced by Lanyon, also in the 1960s. These studies in a variety of bones in a number of species demonstrated remarkable uniformity in the peak strains and maximum strain rates experienced.Experiments combining strain gauge instrumentation with artificial loading in sheep, pigs, roosters, turkeys, rats and mice has yielded significant insight into the control of strain-related adaptive (re)modeling. This diversity of approach has been largely superseded by non-invasive transcutaneous loading in rats and mice which is now the model of choice for many studies. Together such studies have demonstrated that; over the physiological strain range, bone’s mechanically-adaptive processes are responsive to dynamic but not static strains; the size and nature of the adaptive response controlling bone mass is linearly related to the peak loads encountered; the strain-related response is preferentially sensitive to high strain rates and unresponsive to static ones; is most responsive to unusual strain distributions; is maximized by remarkably few strain cycles and that these are most effective when interrupted by short periods of rest between them

What are the ‘active ingredients’ of interventions targeting the public's engagement with antimicrobial resistance and how might they work?

Objectives. Changing public awareness of antimicrobial resistance (AMR) represents a global public health priority. A systematic review of interventions that targeted public AMR awareness and associated behaviour was previously conducted. Here, we focus on identifying the active content of these interventions and explore potential mechanisms of action. Methods. The project took a novel approach to intervention mapping utilizing the following steps: (1) an exploration of explicit and tacit theory and theoretical constructs within the interventions using the Theoretical Domains Framework (TDFv2), (2) retrospective coding of behaviour change techniques (BCTs) using the BCT Taxonomy v1, and (3) an investigation of coherent links between the TDF domains and BCTs across the interventions. Results. Of 20 studies included, only four reported an explicit theoretical basis to their intervention. However, TDF analysis revealed that nine of the 14 TDF domains were utilized, most commonly ‘Knowledge’ and ‘Environmental context and resources’. The BCT analysis showed that all interventions contained at least one BCT, and 14 of 93 (15%) BCTs were coded, most commonly ‘Information about health consequences’, ‘Credible source’, and ‘Instruction on how to perform the behaviour’. Conclusions. We identified nine relevant TDF domains and 14 BCTs used in these interventions. Only 15% of BCTs have been applied in AMR interventions thus providing a clear opportunity for the development of novel interventions in this context. This methodological approach provides a useful way of retrospectively mapping theoretical constructs and BCTs when reviewing studies that provide limited information on theory and intervention content

Pomegranate extract supplementation on neuromuscular performance during resistance exercise

Dietary nitrate supplementation has been shown to improve skeletal muscle function during high-velocity and high-power contractions due to its high nitrate levels; however, there is limited data examining its potential in exercise requiring these movements, such as resistance exercise. Nitrate supplementation has been studied extensively as beetroot juice, but its poor taste severely limits its application. Pomegranate extract (POM) may be an alternative nitrate source due to its superior taste, high nitrate content, and additional antioxidants but has yet to be explored. The purpose of the present study is two-fold: 1) to determine the nitrate concentration in POM; and 2) to examine the effect of POM supplementation on neuromuscular performance during resistance exercise. In phase 1, the concentration of nitrate in commercially available pomegranate products was quantified to guide dosing regimens for phase 2. During Phase 2, in a double-blind, randomized, crossover design, 15 healthy recreationally active males and females will arrive to the laboratory for 5 visits over 3-4 weeks. Participants will perform a one repetition maximum test followed by a familiarization to the protocol. Following this, participants will perform 3 experimental conditions by consuming: 1) empty capsules containing negligible nitrate (PL); 2) a conventional dose of nitrate (POM-NORM, 9 mmol of nitrate); and 3) a high dose of nitrate (POM-HIGH, 13.5 mmol of nitrate) ~2.5 hours prior to exercise testing. During experimental visits, a resting blood draw will be obtained, then subjects will perform a protocol for determining power during countermovement jumps, kneeling countermovement pushups, and back squats. Muscle power will be determined by using a force plate and linear transducer. Results for Phase 1 of the study showed that POM extract contained 2.2 mmol of nitrate per gram of the 200 mg/mL extract. Therefore, it is recommended that participants ingest 6 capsules for 9 mmol of nitrate or 9 capsules for 13.5 mmol of nitrate. Phase 2 is in the data collection phase and ongoing

Minerals Form a Continuum Phase in Mature Cancellous Bone

Bone is a hierarchically structured composite consisting of a protein phase (type I collagen) and a mineral phase (carbonated apatite). The objective of this study was to investigate the hierarchical structure of mineral in mature bone. A method to completely deproteinize bone without altering the original structure is developed, and the completion is confirmed by protein analysis techniques. Stereoscopy and field emission electron microscopy are used to examine the structural features from submillimeter- to micrometer- to nanometer-length scales of bovine femur cancellous bone. Stereoscopic images of fully deproteinized and demineralized bovine femur cancellous bone samples show that fine trabecular architecture is unaltered and the microstructural features are preserved, indicating the structural integrity of mineral and protein constituents. SEM revealed that bone minerals are fused together and form a sheet-like structure in a coherent manner with collagen fibrils. Well-organized pore systems are observed at varying hierarchical levels. Mineral sheets are peeled off and folded after compressive deformation, implying strong connection between individual crystallites. Results were compared with commercially available heat-deproteinized bone (Bio-Oss®), and evidence showed consistency in bone mineral structure. A two-phase interpenetrating composite model of mature bone is proposed and discussed

Does repetitive task training improve functional activity after stroke? A Cochrane systematic review and meta-analysis.

Repetitive task training resulted in modest improvement across a range of lower limb outcome measures, but not upper limb outcome measures. Training may be sufficient to have a small impact on activities of daily living. Interventions involving elements of repetition and task training are diverse and difficult to classify: the results presented are specific to trials where both elements are clearly present in the intervention, without major confounding by other potential mechanisms of action

Age-Related Impairment of Bones' Adaptive Response to Loading in Mice is Associated with Sex-Related Deficiencies in Osteoblasts But No Change in Osteocytes

Bones adjust their mass and architecture to be sufficiently robust to withstand functional loading by adapting to their strain environment. This mechanism appears less effective with age, resulting in low bone mass. In male and female young adult (17-week-old) and old (19-month-old) mice, we investigated the effect of age in vivo on bones' adaptive response to loading and in vitro in primary cultures of osteoblast-like cells derived from bone cortices. Right tibias were axially loaded on alternate days for 2 weeks. Left tibias were non-loaded controls. In a separate group, the number of sclerostin-positive osteocytes and the number of periosteal osteoblasts were analyzed 24 hours after a single loading episode. The responses to strain of the primary osteoblast-like cells derived from these mice were assessed by EGR2 expression, change in cell number and Ki67 immunofluorescence. In young male and female mice, loading increased trabecular thickness and the number of trabecular connections. Increase in the number of trabecular connections was impaired with age but trabecular thickness was not. In old mice, the loading-related increase in periosteal apposition of the cortex was less than in young ones. Age was associated with a lesser loading-related increase in osteoblast number on the periosteal surface but had no effect on loading-related reduction in the number of sclerostin-positive osteocytes. In vitro, strain-related proliferation of osteoblast-like cells was lower in cells from old than young mice. Cells from aged female mice demonstrated normal entry into the cell cycle but subsequently arrested in G2 phase, reducing strain-related increases in cell number. Thus, in both male and female mice, loading-related adaptive responses are impaired with age. This impairment is different in females and males. The deficit appears to occur in osteoblasts' proliferative responses to strain rather than earlier strain-related responses in the osteocytes

Disuse rescues the age-impaired adaptive response to external loading in mice

UNLABELLED: We aimed to determine whether aged bones diminished response to mechanical loading could be rescued by modulating habitual activity. By reducing background loading, aged bones response to loading increased to a level no different to young mice. This suggests, given the right stimulus, that ageing bone can respond to mechanical loading. INTRODUCTION: Age-related decline in bone mass has been suggested to represent an impaired ability of bone to adapt to its mechanical environment. In young mice, the tibias response to external mechanical loading has been shown to increase when habitual activity is reduced by sciatic neurectomy. Here we investigate if neurectomy can rescue bones response to loading in old mice. METHODS: The effect of tibial disuse, induced by unilateral sciatic neurectomy (SN), on the adaptive response to a single peak magnitude of dynamic load-engendered mechanical strain was assessed in 19-month-old (aged) mice. In a second experiment, a range of peak loads was used to assess the load magnitude-related effects of loading on a background of disuse in young adult and aged mice. Bone architecture was analysed using micro-computed tomography (μCT) and dynamic histomorphometry. RESULTS: In the first experiment, SN in aged mice was associated with a significant periosteal osteogenic response to loading not observed in sham-operated mice (7.98 ± 1.7 vs 1.02 ± 2.2 % increase in periosteally enclosed area, p &lt; 0.05). In the second experiment, SN abrogated the expected age-related difference in the bones osteogenic response to peak strain magnitude (p &gt; 0.05). CONCLUSIONS: These data suggest that bones age-related decline in osteogenic responsiveness to loading does not originate in bone cells to either assess, or appropriately respond to strain, but rather is likely to be due to inhibitory averaging effects derived from the habitual strains to which the bone is already adapted. If such strain averaging is applicable to humans, it suggests that gentle exercise may degrade the beneficially osteogenic effects of short periods of more vigorous activity

Exercise does not enhance aged bone's impaired response to artificial loading in C57Bl/6 mice

AbstractBones adapt their structure to their loading environment and so ensure that they become, and are maintained, sufficiently strong to withstand the loads to which they are habituated. The effectiveness of this process declines with age and bones become fragile fracturing with less force. This effect in humans also occurs in mice which experience age-related bone loss and reduced adaptation to loading. Exercise engenders many systemic and local muscular physiological responses as well as engendering local bone strain. To investigate whether these physiological responses influence bones' adaptive responses to mechanical strain we examined whether a period of treadmill exercise influenced the adaptive response to an associated period of artificial loading in young adult (17-week) and old (19-month) mice. After treadmill acclimatization, mice were exercised for 30min three times per week for two weeks. Three hours after each exercise period, right tibiae were subjected to 40cycles of non-invasive axial loading engendering peak strain of 2250με. In both young and aged mice exercise increased cross-sectional muscle area and serum sclerostin concentration. In young mice it also increased serum IGF1. Exercise did not affect bone's adaptation to loading in any measured parameter in young or aged bone. These data demonstrate that a level of exercise sufficient to cause systemic changes in serum, and adaptive changes in local musculature, has no effect on bone's response to loading 3h later. This study provides no support for the beneficial effects of exercise on bone in the elderly being mediated by systemic or local muscle-derived effects rather than local adaptation to altered mechanical strain