Abstract Osteocytes locally remodel their surrounding tissue through perilacunar canalicular remodeling (PLR). During lactation, osteocytes remove minerals to satisfy the metabolic demand, resulting ...in increased lacunar volume, quantifiable with synchrotron X-ray radiation micro-tomography (SRµCT). Although the effects of lactation on PLR are well-studied, it remains unclear whether PLR occurs uniformly throughout the bone and what mechanisms prevent PLR from undermining bone quality. We used SRµCT imaging to conduct an in-depth spatial analysis of the impact of lactation and osteocyte-intrinsic MMP13 deletion on PLR in murine bone. We found larger lacunae undergoing PLR are located near canals in the mid-cortex or endosteum. We show lactation-induced hypomineralization occurs 14 µm away from lacunar edges, past a hypermineralized barrier. Our findings reveal that osteocyte-intrinsic MMP13 is crucial for lactation-induced PLR near lacunae in the mid-cortex but not for whole-bone resorption. This research highlights the spatial control of PLR on mineral distribution during lactation.
Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current ...lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy−/−), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.
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•TGF-β is an osteocyte-intrinsic regulator of perilacunar/canalicular remodeling (PLR)•Osteocytes actively maintain bone quality through regulated control of PLR•Osteocytic PLR is the cellular mechanism by which TGF-β controls bone quality•Defects in PLR cause severe bone fragility, even when bone mass is normal
Resistance to fracture requires healthy bone mass and quality. However, the cellular mechanisms regulating bone quality are unclear. Dole et al. show that osteocyte-intrinsic TGF-β signaling maintains bone quality through perilacunar/canalicular remodeling. Thus, osteocytes mediate perilacunar/canalicular remodeling and osteoclast-directed remodeling to cooperatively maintain bone quality and mass and prevent fragility.
The prevention of fragility fractures in bone-pathologic fractures resulting from daily activity and mostly occurring in the elderly population-has been a long-term clinical quest. Recent research ...indicating that falls in the elderly might be the consequence of fracture rather than its cause has raised fundamental questions about the origin of fragility fractures. Is day-to-day cyclic loading, instead of a single-load event such as a fall, the main cause of progressively growing fractures? Are fragility fractures predominantly affected by bone quality rather than bone mass, which is the clinical indicator of fracture risk? Do osteocytes actively participate in the bone repair process? In this Perspective, we discuss the central role of cyclic fatigue in bone fragility fracture.
Osteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to ...subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicular remodeling (PLR) was most severe in the medial compartment of OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. As a step toward evaluating the causality of PLR suppression in OA, we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact, using Cre recombinase driven by the 9.6-kb DMP1 promoter. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content, change chondrocyte production of collagen II, aggrecan, and MMP13, and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, defects in PLR coincide with cartilage defects. Osteocyte-derived MMP13 emerges as a critical regulator of cartilage homeostasis, likely via its effects on PLR. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis.
The qualitative study presented here shows how a secondary school history teacher in the United Kingdom transformed her lesson planning and classroom interactions with students following professional ...development in the genre-based Reading to Learn pedagogy grounded in Systemic Functional Linguistics. The teacher undertook Reading to Learn while teaching a history class preparing for the General Certificate of Secondary Education. The professional development enabled her to analyse the genres and linguistic features of history texts in order to support the development of subject knowledge via the implementation of the teaching strategies designed to support student reading and writing of the texts required by the examination curriculum. The study reporting on the teacher planning and classroom practices includes examples of teacher-student interaction that demonstrate how the teacher was able to approach her disciplinary texts through the lens of genre, thus identifying the existing gap between the reading of informative genres in textbooks and the requirement to write in less familiar evaluative genres in exams. Moreover, the careful planning of strategies to support reading and the annotation of texts, had a positive impact on the joint construction of the less familiar argumentative genre required.
Abstract
When studying bone fragility diseases, it is difficult to identify which factors reduce bone’s resistance to fracture because these diseases alter bone at many length scales. Here, we ...investigate the contribution of nanoscale collagen behavior on macroscale toughness and microscale toughening mechanisms using a bovine heat-treatment fragility model. This model is assessed by developing an in situ toughness testing technique for synchrotron radiation micro-computed tomography to study the evolution of microscale crack growth in 3D. Low-dose imaging is employed with deep learning to denoise images while maintaining bone’s innate mechanical properties. We show that collagen damage significantly reduces macroscale toughness and post-yield properties. We also find that bone samples with a compromised collagen network have reduced amounts of crack deflection, the main microscale mechanism of fracture resistance. This research demonstrates that collagen damage at the nanoscale adversely affects bone’s toughening mechanisms at the microscale and reduces the overall toughness of bone.
The role of collagen in the dermal armor of the boxfish Garner, Sean N.; Naleway, Steven E.; Hosseini, Maryam S. ...
Journal of materials research and technology,
November-December 2020, 2020-11-00, 2020-11-01, Letnik:
9, Številka:
6
Journal Article
Recenzirano
Odprti dostop
This research aims to further the understanding of the structure and mechanical properties of the dermal armor of the boxfish (Lactoria cornuta). Structural differences between collagen regions ...underlying the hexagonal scutes were observed with confocal microscopy and microcomputed tomography (μ-CT). μ-CT revealed a tapering of the mineral plate from the center of the scute to the interface between scutes, suggesting the structure allows for more flexibility at the interface. High-resolution μ-CT revealed, for the first time, a 3D image of the dermal armor’s complex collagen structure. Helical interfibrillar gaps in the collagen base were found that are similar to the Bouligand-type structure of the lobster, Homarus americanus, thereby suggesting that the collagen in the boxfish is also of a Bouligand-type structure. In situ scanning electron microscopy tests were performed in shear and tension between two connected scutes and suggest that the interfacial collagen is structurally designed to preferentially absorb energy during deformation to protect the internal collagen. Similarly, in situ small-angle x-ray scattering was performed in shear and tension and further corroborated the complex collagen structure. Lastly, these experimental results are coupled with finite element simulations that characterize the interfacial collagen and corroborate the non-linear deformation response seen during in situ testing. Overall, these findings further the understanding of the structure and mechanics of the dermal armor of the boxfish which may help provide a basis to synthesize bioinspired composites for impact-resistant materials, specifically with bioinspired Bouligand-type structures to create novel fiber-reinforced composites.
Type 2 diabetes mellitus (T2DM) is associated with an increased fracture risk independent of bone mass. The exact origin of this increased fracture remains to be fully understood. Using a polygenic ...diabetic Zucker Diabetic Sprague Dawley (ZDSD) rat model, synchrotron radiation micro-computed tomography imaging (SRµCT), and in situ scanning electron microscope (SEM) fracture toughness test, we related the changes at the microscale to toughness and material properties of diabetic rat femurs. As expected, the diabetic rat model displayed overnight fasting hyperglycemia, increased advanced glycation end-product (AGE) content, and reduced crack growth toughness. At the microscale level, our data revealed deficits in vascular canal and osteocyte lacunae structure. T2DM significantly decreased the canal density by 31%, the lacunar density by 16%, and the lacunar volume by 14%. These microstructural deficits can partially explain the 55% reduction in crack growth fracture resistance; these extrinsic toughening mechanisms use microstructural features to dissipate energy. This drop in fracture resistance can also be attributed to decreased post-yield properties with AGE concentration in diabetes. Reduction in osteocyte density is an indicator of alteration of cellular activity and bone quality. In conclusion, we showed that changes in lacunae and canal density, combined with loss of material properties due to AGE accumulation, decreased toughness in T2DM rat bone.
Advanced-Glycation-Endproducts (AGEs) are known to be a major cause of impaired tissue material properties. In collagen fibrils, which constitute a major building component of human tissue, these ...AGEs appear as fibrillar cross-links. It has been shown that when AGEs accumulate in collagen fibrils, a process often caused by diabetes and aging, the mechanical properties of the collagen fibril are altered. However, current knowledge about the mechanical properties of different types of AGEs, and their quantity in collagen fibrils is limited owing to the scarcity of available experimental data. Consequently, the precise relationship between the nano-scale cross-link properties, which differ from type to type, their density in collagen fibrils, and the mechanical properties of the collagen fibrils at larger scales remains poorly understood. In our study, we use coarse-grained molecular dynamics simulations and perform destructive tensile tests on collagen fibrils to evaluate the effect of different cross-link densities and their mechanical properties on collagen fibril deformation and fracture behavior. We observe that the collagen fibril stiffens at high strain levels when either the AGEs density or the loading energy capacity of AGEs are increased. Based on our results, we demonstrate that this stiffening is caused by a mechanism that favors energy absorption via stretching rather than inter-molecular sliding. Hence, in these cross-linked collagen fibrils, the absorbed energy is stored rather than dissipated through friction, resulting in brittle fracture upon fibrillar failure. Further, by varying multiple AGEs nano-scale parameters, we show that the AGEs loading energy capacity is, aside from their density in the fibril, the unique factor determining the effect of different types of AGEs on the mechanical behavior of collagen fibrils. Our results show that knowing AGEs properties is crucial for a better understanding of the nano-scale origin of impaired tissue behavior. We further suggest that future experimental investigations should focus on the quantification of the loading energy capacity of AGEs as a key property for their influence on collagen fibrils.
•Higher bond breaking distance and stiffness cause collagen stiffening.•The stiffening of the fibril is caused by reduced sliding between tropocollagens.•Decreased sliding leads to less energy dissipation.•When inter-molecular sliding is reduced, stretching of the tropocollagens increases.•More stretching leads to energy absorption in the tropocollagens and brittle failure.
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