Rapid correction of chronic hyperglycemia and bone remodeling,warning against overdoing

It is widely recognized that chronic hyperglycemia decreases bone quality,although little is known about the impact of the rapid correction of chronic hyperglycemia on the quality of bone remodeling.This spotlight article explores this correlation by focusing on the stages of bone remodeling linked to glucose levels.

Adjusting phosphate feeding regimen according to daily rhythm increases eggshell quality via enhancing medullary bone remodeling in laying hens

Background Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle.The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms.There is lack of information about the impact of adjusting phosphate feeding regimen according to daily rhythm on the phosphorus homeostasis and bone remodeling of laying hens.Methods and results Two experiments were conducted.In Exp.1,Hy-Line Brown laying hens(n=45)were sampled according the oviposition cycle(at 0,6,12,and 18 h post-oviposition,and at the next oviposition,respectively;n=9 at each time point).Diurnal rhythms of body calcium/phosphorus ingestions and excretions,serum calcium/phosphorus levels,oviduct uterus calcium transporter expressions,and medullary bone(MB)remodeling were illustrated.In Exp.2,two diets with different phosphorus levels(0.32%and 0.14%non-phytate phosphorus(NPP),respectively)were alternately presented to the laying hens.Briefly,four phosphorus feeding regimens in total(each included 6 replicates of 5 hens):(1)fed 0.32%NPP at both 09:00 and 17:00;(2)fed 0.32%NPP at 09:00 and 0.14%NPP at 17:00;(3)fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00;(4)fed 0.14%NPP at both 09:00 and 17:00.As a result,the regimen fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00,which was designed to strengthen intrinsic phosphate circadian rhythms according to the findings in Exp.1,enhanced(P<0.05)MB remodeling(indicated by histological images,serum markers and bone mineralization gene expressions),elevated(P<0.05)oviduct uterus calcium transportation(indicated by transient receptor potential vanilloid 6 protein expression),and subsequently increased(P<0.05)eggshell thickness,eggshell strength,egg specific gravity and eggshell index in laying hens.Conclusions These results underscore the importance of manipulating the sequence of daily phosphorus ingestion,instead of simply controlling dietary phosphate concentrations,in modifying the bone remodeling process.Body phosphorus rhythms will need to be maintained during the daily eggshell calcification cycle.

Fractional Order Nonlinear Bone Remodeling Dynamics Using the Supervised Neural Network

This study aims to solve the nonlinear fractional-order mathematical model(FOMM)by using the normal and dysregulated bone remodeling of themyeloma bone disease(MBD).For themore precise performance of the model,fractional-order derivatives have been used to solve the disease model numerically.The FOMM is preliminarily designed to focus on the critical interactions between bone resorption or osteoclasts(OC)and bone formation or osteoblasts(OB).The connections of OC and OB are represented by a nonlinear differential system based on the cellular components,which depict stable fluctuation in the usual bone case and unstable fluctuation through the MBD.Untreated myeloma causes by increasing the OC and reducing the osteoblasts,resulting in net bone waste the tumor growth.The solutions of the FOMM will be provided by using the stochastic framework based on the Levenberg-Marquardt backpropagation(LVMBP)neural networks(NN),i.e.,LVMBPNN.The mathematical performances of three variations of the fractional-order derivative based on the nonlinear disease model using the LVMPNN.The static structural performances are 82%for investigation and 9%for both learning and certification.The performances of the LVMBPNN are authenticated by using the results of the Adams-Bashforth-Moulton mechanism.To accomplish the capability,steadiness,accuracy,and ability of the LVMBPNN,the performances of the error histograms(EHs),mean square error(MSE),recurrence,and state transitions(STs)will be provided.

The role of exosomes in bone remodeling and osseointegration of implants

Dental implant is an effective method in the treatment of missing teeth.The process of osseointegration of implant teeth involves the coordinated operation of immune system and bone system.The interaction between cells is closely related to bone formation and repair.Exosomes are important intercellular communication molecules.They were originally found in the supernatant of sheep erythrocytes cultured in vitro.They are micro vesicles with a diameter of 40~150 nm.They exist in a variety of cells and body fluids.They enter the target cells by endocytosis and transport,affecting the expression of cell genes and changing the fate of cells.It has an important regulatory function in the microenvironment of implant bone binding.It plays a role in bone remodeling through small molecular RNA,specific proteins and other growth factors secreted by different cells.This article reviews the role of bone derived cellderived exosomes in bone remodeling and their function in implant osseointegration.

The role of microRNAs in bone remodeling

Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that micro RNAs（mi RNAs）, known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression,and growing numbers of novel mi RNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis,and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of mi RNAs in regulating bone remodeling as well as novel applications for mi RNAs in biomaterials for therapeutic purposes.

Autophagy in fate determination of mesenchymal stem cells and bone remodeling

Mesenchymal stem cells(MSCs)have been widely exploited as promising candidates in clinical settings for bone repair and regeneration in view of their self-renewal capacity and multipotentiality.However,little is known about the mechanisms underlying their fate determination,which would illustrate their effectiveness in regenerative medicine.Recent evidence has shed light on a fundamental biological role of autophagy in the maintenance of the regenerative capability of MSCs and bone homeostasis.Autophagy has been implicated in provoking an immediately available cytoprotective mechanism in MSCs against stress,while dysfunction of autophagy impairs the function of MSCs,leading to imbalances of bone remodeling and a wide range of aging and degenerative bone diseases.This review aims to summarize the up-to-date knowledge about the effects of autophagy on MSC fate determination and its role as a stress adaptation response.Meanwhile,we highlight autophagy as a dynamic process and a double-edged sword to account for some discrepancies in the current research.We also discuss the contribution of autophagy to the regulation of bone cells and bone remodeling and emphasize its potential involvement in bone disease.

Mechanisms of altered bone remodeling in children with type 1 diabetes

Bone loss associated with type 1 diabetes mellitus(T1DM)begins at the onset of the disease,already in childhood,determining a lower bone mass peak and hence a greater risk of osteoporosis and fractures later in life.The mechanisms underlying diabetic bone fragility are not yet completely understood.Hyperglycemia and insulin deficiency can affect the bone cells functions,as well as the bone marrow fat,thus impairing the bone strength,geometry,and microarchitecture.Several factors,like insulin and growth hormone/insulin-like growth factor 1,can control bone marrow mesenchymal stem cell commitment,and the receptor activator of nuclear factor-κB ligand/osteoprotegerin and Wnt-b catenin pathways can impair bone turnover.Some myokines may have a key role in regulating metabolic control and improving bone mass in T1DM subjects.The aim of this review is to provide an overview of the current knowledge of the mechanisms underlying altered bone remodeling in children affected by T1DM.

LRP6 in mesenchymal stem cells is required for bone formation during bone growth and bone remodeling

Lipoprotein receptor-related protein 6 （LRP6） plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells （MSCs）, skeletal stem cells that give rise to osteoblastic lineage, is unknown. In this study, we generated mice lacking LRP6 expression specifically in nestin＋ MSCs by crossing nestin-Cre mice with LRP6 flox mice and investigated the functional changes of bone marrow MSCs and skeletal alterations. Mice with LRP6 deletion in nestin＋ cells demonstrated reductions in body weight and body length at I and 3 months of age. Bone architecture measured by microCT （uCT） showed a significant reduction in bone mass in both trabecular and cortical bone of homozygous and heterozygous LRP6 mutant mice. A dramatic reduction in the numbers of osteoblasts but much less significant reduction in the numbers of osteoclasts was observed in the mutant mice. Osterix＋ osteoprogenitors and osteocalcin＋ osteoblasts significantly reduced at the secondary spongiosa area, but only moderately decreased at the primary spongiosa area in mutant mice. Bone marrow MSCs from the mutant mice showed decreased colony forming, cell viability and cell proliferation. Thus, LRP6 in bone marrow MSCs is essential for their survival and proliferation, and therefore, is a key positive regulator for bone formation during skeletal growth and remodeling.

Abnormal subchondral bone remodeling and its association with articular cartilage degradation in knees of type 2 diabetes patients

Type 2 diabetes （T2D） is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis （OA）. Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic （n---70） and diabetes （n = 51） groups. Tibial plateaus were also collected from cadaver donors （n = 20） and used as controls. Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase （TRAP）, osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International （OARSI） scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP~ osteoclasts and lower number of Osterix~ osteoprogenitors and Osteocalcin~ osteoblasts. T2D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2D-associated knee OA.

A mathematical model of cortical bone remodeling at cellular level under mechanical stimulus

A bone cell population dynamics model for cor- tical bone remodeling under mechanical stimulus is devel- oped in this paper. The external experiments extracted from the literature which have not been used in the creation of the model are used to test the validity of the model. Not only can the model compare reasonably well with these ex- perimental results such as the increase percentage of final values of bone mineral content （BMC） and bone fracture en- ergy （BFE） among different loading schemes （which proves the validity of the model）, but also predict the realtime devel- opment pattern of BMC and BFE, as well as the dynamics of osteoblasts （OBA）, osteoclasts （OCA）, nitric oxide （NO） and prostaglandin E2 （PGE2） for each loading scheme, which can hardly be monitored through experiment. In conclusion, the model is the first of its kind that is able to provide an in- sight into the quantitative mechanism of bone remodeling at cellular level by which bone cells are activated by mechan- ical stimulus in order to start resorption/formation of bone mass. More importantly, this model has laid a solid foun- dation based on which future work such as systemic control theory analysis of bone remodeling under mechanical stimu- lus can be investigated. The to-be identified control mecha- nism will help to develop effective drugs and combined non- pharmacological therapies to combat bone loss pathologies. Also this deeper understanding of how mechanical forces quantitatively interact with skeletal tissue is essential for the generation of bone tissue for tissue replacement purposes in tissue engineering.

Bone remodeling in sigmoid sinus diverticulum after stenting for transverse sinus stenosis in pulsatile tinnitus: A case report

BACKGROUND Pulsatile tinnitus(PT)is a potentially disabling symptom that has received increasing attention.Multiple causes of PT have been confirmed by targeted treatment.However,dynamic changes of related structures in PT patients with multiple causes after stenting for ipsilateral transverse sinus stenosis(TSS)have not been previously reported.We report such a case and present postoperative computed tomography venography(CTV)follow-up findings to demonstrate the decreased sigmoid sinus diverticulum and bone remodeling.CASE SUMMARY A 45-year-old man suffered from left-sided PT for 15 years that was occasionally accompanied by headache and dizziness.Pre-operative CTV revealed left-sided sigmoid sinus wall anomalies(SSWAs),TSS,outflow dominance,large posterior condylar emissary vein,and an empty sella turcica.A cerebrospinal fluid pressure of 270 mmH2O was further detected.The sound disappeared immediately after stenting for ipsilateral TSS,with no recurrence during 2 years of follow-up.After the procedure,the patient underwent four consecutive CTV examinations.The diverticulum decreased 6 mo after the procedure with new bone remodeling.The density of the remodeled bone was further increased 1 year later,and a hardened edge was formed 2 years later.CONCLUSION PT associated with SSWAs,TSS,and idiopathic intracranial hypertension can be cured by stenting for TSS alone.And bone remodeling around SSWAs is a more significant finding.

Parametric study of control mechanism of cortical bone remodeling under mechanical stimulus

The control mechanism of mechanical bone remodeling at cellular level was investigated by means of an extensive parametric study on a theoretical model described in this paper. From a perspective of control mechanism, it was found that there are several control mechanisms working simultaneously in bone remodeling which is a complex process. Typically, an extensive parametric study was carried out for investigating model parameter space related to cell differentiation and apoptosis which can describe the fundamental cell lineage behaviors. After analyzing all the combinations of 728 permutations in six model parameters, we have identified a small number of parameter combinations that can lead to physiologically realistic responses which are similar to theoretically idealized physiological responses. The results presented in the work enhanced our understanding on mechanical bone remodeling and the identified control mechanisms can help researchers to develop combined pharmacological-mechanical therapies to treat bone loss diseases such as osteoporosis.

Bone Remodeling, Biomaterials And Technological Applications: Revisiting Basic Concepts

Presently, several different graft materials are employed in regenerative or corrective bone surgery. However current misconceptions about these biomaterials, their use and risks may compromise their correct application and development. To unveil these misconceptions, this work briefly reviewed concepts about bone remodeling, grafts classification and manufacturing processes, with a special focus on calcium phosphate materials as an example of a current employed biomaterial. Thus a search on the last decade was performed in Medline, LILACS, Scielo and other scientific electronic libraries using as keywords biomaterials, bone remodeling, regeneration, biocompatible materials, hydroxyapatite and therapeutic risks. Our search showed not only an accelerated biotechnological development that brought significant advances to biomaterials use on bone remodeling treatments but also several therapeutic risks that should not be ignored. The biomaterials specificity and limitations to clinical application point to the current need for developing safer products with better interactions with the biological microenvironments.

Numerical Simulation of Bone Remodeling Coupling the Damage Repair Process in Human Proximal Femur

Microdamage is produced in bone tissue under the long-termeffects of physiological loading,as well as age,disease and other factors.Bone remodeling can repair microdamage,otherwise this damage will undermine bone quality and even lead to fractures.In this paper,the damage variable was introduced into the remodeling algorithm.The new remodeling algorithm contains a quadratic term that can simulate reduction in bone density after large numbers of loading cycles.The model was applied in conjunction with the 3Dfinite elementmethod(FEM)to the remodeling of the proximal femur.The results showed that the initial accumulation of fatigue damage led to an increase in density but when the damage reached a certain level,the bone density decreased rapidly until the femur failed.With the accumulation of damage,bone remodeling was coupled with fatigue damage to maintain the function of bone.When the accumulation of damage reached a certain level,bone remodeling failed to repair the accumulated fatigue damage in time,and continued cyclic loading significantly weakened the loadbearing capacity of the bone.The new mathematical model not only predicts fatigue life,but also helps to further understand the compromise between damage repair and damage accumulation,which is of great significance for the prevention and treatment of clinical bone diseases.

Evaluation of bone remodeling in regard to the age of scaphoid non-unions

AIM: To analyse bone remodeling in regard to the age of scaphoid non-unions(SNU) with immunohistochemistry.METHODS: Thirty-six patients with symptomatic SNU underwent surgery with resection of the pseudarthrosis. The resected material was evaluated histologically after staining with hematoxylin-eosin(HE), tartrate resistant acid phosphatase(TRAP), CD 68, osteocalcin(OC) and osteopontin(OP). Histological examination was performed in a blinded fashion.RESULTS: The number of multinuclear osteoclasts in the TRAP-staining correlated with the age of the SNU and was significantly higher in younger SNU(P = 0.034; r = 0.75). A higher number of OP-immunoreactive osteoblasts significantly correlated with a higher number of OC-immunoreactive osteoblasts(P = 0.001; r = 0.55). Furthermore, a greater number of OP-immunoreactive osteoblasts correlated significantly with a higher number of OP-immunoreactive multinuclear osteoclasts(P = 0.008; r = 0.43). SNU older than 6 mo showed a signifi-cant decrease of the number of fibroblasts(P = 0.04). Smoking and the age of the patients had no influence on bone remodeling in SNU.CONCLUSION: Multinuclear osteoclasts showed a significant decrease in relation to the age of SNU. However, most of the immunhistochemical findings of bone remodeling do not correlate with the age of the SNU. This indicates a permanent imbalance of bone formation and resorption as indicated by a concurrent increase in both osteoblast and osteoclast numbers. A clear histological differentiation into phases of bone remodeling in SNU is not possible.

Analysis of Bone Remodeling Under Piezoelectricity Effects Using Boundary Elements

Piezoelectric materials exhibit a response to mechanical-electrical coupling, which represents an important contribution to the electrical-mechanical interaction in bone remodeling process. Therefore, the study of the piezoelectric effect on bone re- modeling has high interest in applied biomechanics. The effects of mechano-regulation and electrical stimulation on bone healing are explained. The Boundary Element Method （BEM） is used to simulate piezoelectric effects on bones when shearing forces are applied to collagen fibers to make them slip past each other. The piezoelectric fundamental solutions are obtained by using the Radon transform. The Dual Reciprocity Method （DRM） is used to simulate the particular solutions in time-dependent problems. BEM analysis showed the strong influence of electrical stimulation on bone remodeling. The examples discussed in this work showed that, as expected, the electrically loaded bone surfaces improved the bone deposition. BEM results confirmed previous findings obtained by using the Finite Element Method （FEM）. This work opens very promising doors in biomechanics research, showing that mechanical loads can be replaced, in part, by electrical charges that stimulate strengthening bone density. The obtained results herein are in good agreement with those found in literature from experimental testing and/or other simu- lation approaches.

A Femur-Implant Model for the Prediction of Bone Remodeling Behavior Induced by Cementless Stem

Bone remodeling simulation is an effective tool for the prediction of long-term effect of implant on the bone tissue, as well as the selection of an appropriate implant in terms of architecture and material. In this paper, a finite element model of proximal femur was developed to simulate the structures of internal trabecular and cortical bones by incorporating quantitative bone functional adaptation theory with finite element analysis. Cementless stems made of titanium, two types of Functionally Graded Material （FGM） and flexible ＇iso-elastic＇ material as comparison were implanted in the structure of proximal femur respectively to simulate the bone remodeling behaviors of host bone. The distributions of bone density, von Mises stress, and interface shear stress were obtained. All the prosthetic stems had effects on the bone remodeling behaviors of proximal femur, but the degrees of stress shielding were different. The amount of bone loss caused by titanium implant was in agreement with the clinical obser- vation. The FGM stems caused less bone loss than that of the titanium stem, in which FGM I stem （titanium richer at the top to more HAP/Col towards the bottom） could relieve stress shielding effectively, and the interface shear stresses were more evenly distributed in the model with FGM 1 stem in comparison with those in the models with FGM II （titanium and bioglass） and titanium stems. The numerical simulations in the present study provided theoretical basis for FGM as an appropriate material of femoral implant from a biomechanical point of view. The next steps are to fabricate FGM stern and to conduct animal experiments to investigate the effects of FGM stem on the remodeling behaviors using animal model.

A histological and biomechanical study of bone stress and bone remodeling around immediately loaded implants

Immediate loading(IL)increases the risk of marginal bone loss.The present study investigated the biomechanical response of peri-implant bone in rabbits after IL,aiming at optimizing load management.Ninety-six implants were installed bilaterally into femurs of 48 rabbits.Test implants on the left side created the maximal initial stress of 6.9 and 13.4 MPa in peri-implant bone and unloaded implants on the contralateral side were controls.Bone morphology and bone-implant interface strength were measured with histological examination and push-out testing during a 12-week observation period.Additionally,the animal data were incorporated into finite element(FE)models to calculate the bone stress distribution at different levels of osseointegration.Results showed that the stress was concentrated in the bone margin and the bone stress gradually decreased as osseointegration proceeded.A stress of about 2.0 MPa in peri-implant bone had a positive effect on new bone formation,osseointegration and bone-implant interface strength.Bone loss was observed in some specimens with stress exceeding 4.0 MPa.Data indicate that IL significantly increases bone stress during the early postoperative period,but the load-bearing capacity of peri-implant bone increases rapidly with an increase of bone-implant contact.Favorable bone responses may be continually promoted when the stress in peri-implant bone is maintained at a definite level.Accordingly,the progressive loading mode is recommended for IL implants.

Biocompatible reduced graphene oxide stimulated BMSCs induce acceleration of bone remodeling and orthodontic tooth movement through promotion on osteoclastogenesis and angiogenesis

We has synthesized the biocompatible gelatin reduced graphene oxide(GOG)in previous research,and in this study we would further evaluate its effects on bone remodeling in the aspects of osteoclastogenesis and angiogenesis so as to verify its impact on accelerating orthodontic tooth movement.The mouse orthodontic tooth movement(OTM)model tests in vivo showed that the tooth movement was accelerated in the GOG local injection group with more osteoclastic bone resorption and neovascularization compared with the PBS injection group.The analysis on the degradation of GOG in bone marrow stromal stem cells(BMSCs)illustrated its good biocompatibility in vitro and the accumulation of GOG in spleen after local injection of GOG around the teeth in OTM model in vivo also didn’t influence the survival and life of animals.The co-culture of BMSCs with hematopoietic stem cells(HSCs)or human umbilical vein endothelial cells(HUVECs)in transwell chamber systems were constructed to test the effects of GOG stimulated BMSCs on osteoclastogenesis and angiogenesis in vitro.With the GOG stimulated BMSCs co-culture in upper chamber of transwell,the HSCs in lower chamber manifested the enhanced osteoclastogenesis.Meanwhile,the co-culture of GOG stimulated BMSCs with HUVECs showed a promotive effect on the angiogenic ability of HUVECs.The mechanism analysis on the biofunctions of the GOG stimulated BMSCs illustrated the important regulatory effects of PERK pathway on osteoclastogenesis and angiogenesis.All the results showed the biosecurity of GOG and the biological functions of GOG stimulated BMSCs in accelerating bone remodeling and tooth movement.

Bone remodeling effect of a chitosan and calcium phosphate-based composite

Chitosan is a biocompatible polymer that has been widely studied for tissue engineering purposes.The aim of this research was to assess bone regenerative properties of an injectable chitosan and calcium phosphate-based composite and identify optimal degree of deacetylation(%DDA)of the chitosan polymer.Drill holes were generated on the left side of a mandible in Sprague-Dawley rats,and the hole was either left empty or filled with the implant.The animals were sacrificed at several time points after surgery(7–22 days)and bone was investigated using micro-CT and histology.No significant new bone formation was observed in the implants themselves at any time points.However,substantial new bone formation was observed in the rat mandible further away from the drill hole.Morphological changes indicating bone formation were found in specimens explanted on Day 7 in animals that received implant.Similar bone formation pattern was seen in control animals with an empty drill hole at later time points but not to the same extent.A second experiment was performed to examine if the%DDA of the chitosan polymer influenced the bone remodeling response.The results suggest that chitosan polymers with%DDA between 50 and 70%enhance the natural bone remodeling mechanism.