Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with

The vascular endothelium is a dynamic cellular interface between the vessel wall and the bloodstream, where it regulates the physiological effects of humoral and biomechanical stimuli on vessel tone and remodeling. With respect to the latter hemodynamic stimulus, the endothelium is chronically exposed to mechanical forces in the form of cyclic circumferential strain, resulting from the pulsatile nature of blood flow, and shear stress. Both forces can profoundly modulate endothelial cell (EC) metabolism and function and, under normal physiological conditions, impart an atheroprotective effect that disfavors pathological remodeling of the vessel wall. Moreover, disruption of normal hemodynamic loading can be either causative of or contributory to vascular diseases such as atherosclerosis. EC-matrix interactions are a critical determinant of how the vascular endothelium responds to these forces and unquestionably utilizes matrix metalloproteinases (MMPs), enzymes capable of degrading basement membrane and interstitial matrix molecules, to facilitate force-mediated changes in vascular cell fate. In view of the growing importance of blood flow patterns and mechanotransduction to vascular health and pathophysiology, and considering the potential value of MMPs as therapeutic targets, a timely review of our collective understanding of MMP mechanoregulation and its impact on the vascular endothelium is warranted. More specifically, this review primarily summarizes our current knowledge of how cyclic strain regulates MMP expression and activation within the vascular endothelium and subsequently endeavors to address the direct and indirect consequences of this on vascular EC fate. Possible relevance of these phenomena to vascular endothelial dysfunction and pathological remodeling are also addressed.     

Phenomenological model of bone remodeling cycle containing osteocyte regulation loop

Biological parameters, such as bone resorption and formation constants, are important variables to achieve optimised hard tissue scaffolds design. To help to understand the modelling process that occurs when a scaffold is implanted it is vital to understand the rather complex bone remodeling process prevalent in native bone. One approach to developing a mathematical model that predicts osteoactivity both in scaffolds, as well as in bone in vivo, is based on a bio-cybernetic vision of basic multicellular unit (BMU) action -. In the case of the model presented in this paper, an additional loop of regulation based on osteocyte activity has been added. This approach has resulted in a four-dimensional system, which shows steady-quasi-cyclic behaviour using a particular range of constants with real biological meaning. The initial findings suggesting that the basic steady-state appears as a torus in multidimensional phase space have been discussed. The existence of this surface in the osteoclasts-osteoblasts-osteocytes-bone subspace indicates that there is a first integral for this dynamic system. Biological and physical interpretation of this integral as a conservative value has been proposed. It is possible to draw an analogy between this conservative value, as a kind of substrate-energy regenerative potential of the bone remodeling system with a molecular nature, to the classical physical value (energy). There are clear indications that there is recovering potential within the BMU that results in a steady operating genetically predominated bone remodeling process. This recovering potential is directed against both mechanical and biomechanical damage to the bone. The current model has credibility when compared to the normal bone remodeling process. However, additional work is required to study a wider range of constants.     

Osteocyte lacunae tissue strain in cortical bone

Current theories suggest that bone modeling and remodeling are controlled at the cellular level through signals mediated by osteocytes. However, the specific signals to which bone cells respond are still unknown. Two primary theories are: (1) osteocytes are stimulated via the mechanical deformation of the perilacunar bone matrix and (2) osteocytes are stimulated via fluid flow generated shear stresses acting on osteocyte cell processes within canaliculi. Recently, much focus has been placed on fluid flow theories since in vitro experiments have shown that bone cells are more responsive to analytically estimated levels of fluid shear stress than to direct mechanical stretching using macroscopic strain levels measured on bone in vivo. However, due to the complex microstructural organization of bone, local perilacunar bone tissue strains potentially acting on osteocytes cannot be reliably estimated from macroscopic bone strain measurements. Thus, the objective of this study was to quantify local perilacunar bone matrix strains due to macroscopically applied bone strains similar in magnitude to those that occur in vivo. Using a digital image correlation strain measurement technique, experimentally measured bone matrix strains around osteocyte lacunae resulting from macroscopic strains of approximately 2000 microstrain are significantly greater than macroscopic strain on average and can reach peak levels of over 30,000 microstrain locally. Average strain concentration factors ranged from 1.1 to 3.8, which is consistent with analytical and numerical estimates. This information should lead to a better understanding of how bone cells are affected by whole bone functional loading.     

Biological principles of adult degenerative scoliosis

The global aging population has led to an increase in geriatric diseases, including adult degenerative scoliosis (ADS). ADS is a spinal deformity affecting adults, particularly females. It is characterized by asymmetric intervertebral disc and facet joint degeneration, leading to spinal imbalance that can result in severe pain and neurological deficits, thus significantly reducing the quality of life. Despite improved management, molecular mechanisms driving ADS remain unclear. Current literature primarily comprises epidemiological and clinical studies. Here, we investigate the molecular mechanisms underlying ADS, with a focus on angiogenesis, inflammation, extracellular matrix remodeling, osteoporosis, sarcopenia, and biomechanical stress. We discuss current limitations and challenges in the field and highlight potential translational applications that may arise with a better understanding of these mechanisms.     

Anabolic actions of PTH in the skeletons of animals

A brief historical perspective reviews studies that tested the hypotheses that PTH induces an anabolic effect in bone, and that the gain in trabecular bone was not at the expense of cortical bone. As PTH reduces the risk of fracture in humans with osteoporosis, the myths that postulated cortical bone porosity and increased bone turnover might increase fracture risk, are examined in the light of data from animals with osteonal bone. These show that PTH "braces" the bone by immediately stimulating bone formation at modeling and remodeling sites. Increased porosity is a late event, occurring close to the neutral axis of bone where detrimental effects on biomechanical strength are unlikely. PTH increases bone mass by stimulating modeling in favor of bone formation, and restructures bone geometry via more extensive remodeling. Cell and genetic events induced in bone by PTH have been studied in rats and are time- and regimen-dependent. In addition to the stimulation of gene expression for matrix proteins, early genes upregulated by once daily PTH are those associated with matrix degradation and induction of osteoclastic resorption, indicative of possible mechanisms by which PTH may increase bone turnover. Boneforming surfaces are increased due to increased numbers of newly differentiated osteoblasts and retention of older osteoblasts by inhibition of apoptosis. After stopping treatment, the number of osteoblasts is quickly reduced and bone turnover returns to that of controls, slowing both bone formation and resorption. The increased proportion of bone undergoing PTH-induced remodeling requires maturation and completion of mineralization. These responses may explain the delay in reversal of gains in bone mass and biomechanical properties for at least two turnover cycles following withdrawal in large animal models. Thus, the skeletal benefits of PTH extend beyond the active treatment phase.     

Human bone disorders: Pathological role and diagnostic potential of matrix metalloproteinases

Bone undergoes continuous remodeling under physiological and pathological conditions. Failure of the regulation of this process leads to several disorders involving bone erosion. This series of events is mainly based on the action of proteinases, particularly matrix metalloproteinases (MMPs). MMPs have been recently suggested as potential bone resorption markers which could be added to the commonly used ones, in order to predict outcome of disease processes and healing, and to monitor disease response to treatment. As for classical biochemical bone markers, MMPs are far from being applied in primary clinical diagnosis, but they could be promising in some cases for disease prognosis. MMPs as bone remodeling biomarkers could provide information that boosts our understanding of the prognosis, disease activity and pathogenesis of bone disorders. Clarifying the MMPs’ role in bone remodeling and healing could potentially help predict disease progression and the effects of direct specific therapy.     

"Whither flows the fluid in bone?" An osteocyte's perspective

Bone represents a porous tissue containing a fluid phase, a solid matrix, and cells. Movement of the fluid phase within the pores or spaces of the solid matrix translates endogenous and exogenous mechanobiological, biochemical and electromechanical signals from the system that is exposed to the dynamic external environment to the cells that have the machinery to remodel the tissue from within. Hence, bone fluid serves as a coupling medium, providing an elegant feedback mechanism for functional adaptation. Until recently relatively little has been known about bone fluid per se or the influences governing the characteristics of its flow. This work is designed to review the current state of this emerging field. The structure of bone, as an environment for fluid flow, is discussed in terms of the properties of the spaces and channel walls through which the fluid flows and the influences on flow under physiological conditions. In particular, the development of the bone cell syncytium and lacunocanalicular system are presented, and pathways for fluid flow are described from the systemic to the organ, tissue, cellular and subcellular levels. Finally, exogenous and endogenous mechanisms for pressure-induced fluid movement through bone, including mechanical loading, vascular derived pressure gradients, and osmotic pressure gradients are discussed. The objective of this review is to survey the current understanding of the means by which fluid flow in bone is regulated, from the level of the skeletal system down to the level of osteocyte, and to provide impetus for future research in this area of signal transduction and coupling. An understanding of this important aspect of bone physiology has profound implications for restoration of function through innovative treatment modalities on Earth and in space, as well as for engineering of biomimetic replacement tissue.     

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 observation. 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 I 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 stem and to conduct animal experiments to investigate the effects of FGM stem on the remodeling behaviors using animal model.     

Capturing microscopic features of bone remodeling into a macroscopic model based on biological rationales of bone adaptation

To understand Wolff’s law, bone adaptation by remodeling at the cellular and tissue levels has been discussed extensively through experimental and simulation studies. For the clinical application of a bone remodeling simulation, it is significant to establish a macroscopic model that incorporates clarified microscopic mechanisms. In this study, we proposed novel macroscopic models based on the microscopic mechanism of osteocytic mechanosensing, in which the flow of fluid in the lacuno-canalicular porosity generated by fluid pressure gradients plays an important role, and theoretically evaluated the proposed models, taking biological rationales of bone adaptation into account. The proposed models were categorized into two groups according to whether the remodeling equilibrium state was defined globally or locally, i.e., the global or local uniformity models. Each remodeling stimulus in the proposed models was quantitatively evaluated through image-based finite element analyses of a swine cancellous bone, according to two introduced criteria associated with the trabecular volume and orientation at remodeling equilibrium based on biological rationales. The evaluation suggested that nonuniformity of the mean stress gradient in the local uniformity model, one of the proposed stimuli, has high validity. Furthermore, the adaptive potential of each stimulus was discussed based on spatial distribution of a remodeling stimulus on the trabecular surface. The theoretical consideration of a remodeling stimulus based on biological rationales of bone adaptation would contribute to the establishment of a clinically applicable and reliable simulation model of bone remodeling.     

Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass.

Transforming growth factor-beta (TGF-beta) is abundant in bone matrix and has been shown to regulate the activity of osteoblasts and osteoclasts in vitro. To explore the role of endogenous TGF-(beta) in osteoblast function in vivo, we have inhibited osteoblastic responsiveness to TGF-beta in transgenic mice by expressing a cytoplasmically truncated type II TGF-beta receptor from the osteocalcin promoter. These transgenic mice develop an age-dependent increase in trabecular bone mass, which progresses up to the age of 6 months, due to an imbalance between bone formation and resorption during bone remodeling. Since the rate of osteoblastic bone formation was not altered, their increased trabecular bone mass is likely due to decreased bone resorption by osteoclasts. Accordingly, direct evidence of reduced osteoclast activity was found in transgenic mouse skulls, which had less cavitation and fewer mature osteoclasts relative to skulls of wild-type mice. These bone remodeling defects resulted in altered biomechanical properties. The femurs of transgenic mice were tougher, and their vertebral bodies were stiffer and stronger than those of wild-type mice. Lastly, osteocyte density was decreased in transgenic mice, suggesting that TGF-beta signaling in osteoblasts is required for normal osteoblast differentiation in vivo. Our results demonstrate that endogenous TGF-beta acts directly on osteoblasts to regulate bone remodeling, structure and biomechanical properties.     

CTHRC1 promotes osteogenic differentiation of periodontal ligament stem cells by regulating TAZ

Collagen triple helix repeat containing 1 (CTHRC1) is associated with bone metabolism. Alveolar bone has an ability to rapidly remodel itself to adapt its biomechanical environment and function. However, whether CTHRC1 is expressed in alveolar bone tissue and the role of CTHRC1 in alveolar bone remodeling remain unclear. We used orthodontic tooth movement (OTM) rat model to study the effects of CHTRC1 in alveolar bone remodeling in vivo. We found that CTHRC1 was expressed in normal physiological condition of osteocytes, bone matrix, and periodontal ligament cells in rat. During the OTM, the expression of CTHRC1, Runx2 and TAZ were increased. We further studied the effects of CTHRC1 on osteogenic differentiation of human periodontal ligament stem cells in vitro. CTHRC1 can positively regulate the expression of TAZ and osteogenic differentiation markers like Col1, ALP, Runx2 and OCN. Overexpression of CHTRC1 increased osteogenic differentiation of PDLSCs, which could be abolished by TAZ siRNA. Our results suggest that CTHRC1 plays an important role in alveolar bone remodeling and osteogenic differentiation of PDLSCs.     

ATP reduces gel compaction in osteoblast-populated collagen gels.

Bone remodeling is a localized process, but regulated by systemic signals such as hormones, cytokines, and mechanical loading. The mechanism by which bone cells convert these systemic signals into local signals is not completely understood. It is broadly accepted that the "prestress" in cytoskeleton of cells affects the magnitude of cellular responses to mechanical stimuli. Prestress derives from stiff cytoskeletal proteins and their connections within the cell and from cell contractility upon attaching to matrix. In an in vitro model of three-dimensional gel compaction, the relative cellular prestress levels in the same matrix environment were determined by matrix compaction rate: a greater compaction rate resulted in a higher level of prestress. In the present study, the effects of ATP on the prestress of osteoblasts were studied using mouse MC3T3-E1 cells grown in three-dimensional bioartificial tissues (BATs). ATP (> or =100 microM) reduced the compaction rate of BATs in a dose-dependent manner. ADP, 2'-(or 3')-O-(4-benzoylbenzoyl) ATP, and UTP, but not alpha,beta-methylene ATP, also reduced the compaction rate but to a lesser extent. Pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium did not block the effect of ATP on BAT compaction rate. These results indicate that both P2X and P2Y receptors are involved in ATP-induced reduction of BAT compaction rate. Steady fluid flow and RT-PCR results showed that ATP reduced cell attachment on type I collagen by downregulating the expression of integrin alpha(1). These results suggest a potential role for P2 receptors in matrix remodeling and repair and as a potential drug target in treatment of bone diseases.     

Vasculogenesis and angiogenesis: Extracellular matrix remodeling in coronary collateral arteries and the ischemic heart

Heart failure secondary to ischemic cardiomyopathy is the primary cause of cardiovascular mortality. The promise of the collateral circulation lies in its potential to alter the course of the natural history of coronary heart disease. The collateral circulation of the heart is responsible for supplying blood and oxygen to the myocardium at ischemic risk following severe stenosis and reduced vasoelasticity function of a major coronary artery. In response to flow, stress, and pressure, collateral vessels are restructured and remodeled. Vascular remodeling by its very nature implies synthesis and degradation of extracellular matrix components in the vessel wall. Under normal physiological conditions proteinases that break down the specialized matrix are tightly regulated by antiproteinases. The balance between proteinase and antiproteinase influences is discoordinated during collateral development which leads to adaptive changes in the structure, function, and regulation of extracellular matrix components in the vessel wall. The role of extracellular matrix components in coronary collateral vessel formation in a canine model of chronic coronary artery occlusion has been demonstrated. The role of matrix proteinases and antiproteinases in the collateral vessel play a significant role in the underlying mechanisms of collateral development. This review presents new and significant information regarding the role of extracellular matrix proteinases and antiproteinases in vascular remodeling, function, and collateral development. Such information will have a significant impact on the understanding of the basic biology of the vascular extracellular matrix turnover, remodeling, and function as well as on elucidating potential avenues for pharmacological approaches designed to increase collateral formation and optimize myocardial blood flow in the treatment of ischemic heart disease. J. Cell. Biochem. 65:388–394. © 1997 Wiley-Liss, Inc.     

Do Epigenetic Marks Govern Bone Mass and Homeostasis?

Bone is a specialized connective tissue with a calcified extracellular matrix in which cells are embedded. Besides providing the internal support of the body and protection for vital organs, bone also has several important metabolic functions, especially in mineral homeostasis. Far from being a passive tissue, it is continuously being resorbed and formed again throughout life, by a process known as bone remodeling.Bone development and remodeling are influenced by many factors, some of which may be modifiable in the early steps of life. Several studies have shown that environmental factors in uterus and in infancy may modify the skeletal growth pattern, influencing the risk of bone disease in later life. On the other hand, bone remodeling is a highly orchestrated multicellular process that requires the sequential and balanced events of osteoclast-mediated bone resorption and osteoblast-mediated bone formation. These processes are accompanied by specific gene expression patterns which are responsible for the differentiation of the mesenchymal and hematopoietic precursors of osteoblasts and osteoclasts, respectively, and the activity of differentiated bone cells. This review summarizes the current understanding of how epigenetic mechanisms influence these processes and their possible role in common skeletal diseases.     

Effects of Materials of Cementless Femoral Stem on the Functional Adaptation of Bone

The objective of this paper is to identify the effects of materials of cementless femoral stem on the functional adaptive behaviors of bone.The remodeling behaviors of a two-dimensional simplified model of cementless hip prosthesis with stiff stem,flexible 'iso-elastic' stem,one-dimensional Functionally Graded Material (FGM) stem and two-dimensional FGM stem for the period of four years after prosthesis replacement were quantified by incorporating the bone remodeling algorithm with finite element analysis.The distributions of bone density,von Mises stress,and interface shear stress were obtained.The results show that two-dimensional FGM stem may produce more mechanical stimuli and more uniform interface shear stress compared with the stems made of other materials,thus the host bone is well preserved.Accordingly,the two-dimensional FGM stem is an appropriate femoral implant from a biomechanical point of view.The numerical simulation in this paper can provide a quantitative computational paradigm for the changes of bone morphology caused by implants,which can help to improve the design of implant to reduce stress shielding and the risk of bone-prosthesis interface failure.     

Bone phenotype of P2X4 receptor knockout mice: implication of a P2X7 receptor mutation?

Transgenic and knockout animal models are widely used to investigate the role of receptors, signaling pathways, and other peptides and proteins. Varying results are often published on the same model from different groups, and much effort has been put into understanding the underlying causes of these sometimes conflicting results. Recently, it has been shown that a P2X4R knockout model carries a so-called passenger mutation in the P2X7R gene, potentially affecting the interpretation of results from studies using this animal model. We therefore report this case to raise awareness about the potential pitfalls using genetically modified animal models, especially within P2 receptor research. Although purinergic signaling has been recognized as an important contributor to the regulation of bone remodeling, the process that maintains the bone quality during life, little is known about the role of the P2X4 receptor (P2X4R) in regulation of bone remodeling in health and disease. To address this, we analyzed the bone phenotype of P2rx4tm1Rass (C57BL/6J) knockout mice and corresponding wildtype using microCT and biomechanical testing. Overall, we found that the P2X4R knockout mice displayed improved bone microstructure and stronger bones in an age- and gender-dependent manner. While cortical BMD, trabecular BMD, and bone volume were higher in the 6-month-old females and 3-month-old males, this was not the case for the 3-month-old females and the 6-month-old males. Bone strength was only affected in the females. Moreover, we found that P2X4R KO mice carried the P2X7 receptor 451P wildtype allele, whereas the wildtype mice carried the 451L mutant allele. In conclusion, this study suggests that P2X4R could play a role in bone remodeling, but more importantly, it underlines the potential pitfalls when using knockout models and highlights the importance of interpreting results with great caution. Further studies are needed to verify any specific effects of P2X4R on bone metabolism.

     

Numerical analysis of an osseointegrated prosthesis fixation with reduced bone failure risk and periprosthetic bone loss

Currently available implants for direct attachment of prosthesis to the skeletal system after transfemoral amputation (OPRA system, Integrum AB, Sweden and ISP Endo/Exo prosthesis, ESKA Implants AG, Germany) show many advantages over the conventional socket fixation. However, restraining biomechanical issues such as considerable bone loss around the stem and peri-prosthetic bone fractures are present. To overcome these limiting issues a new concept of the direct intramedullary fixation was developed. We hypothesize that the new design will reduce the peri-prosthetic bone failure risk and adverse bone remodeling by restoring the natural load transfer in the femur. Generic CT-based finite element models of an intact femur and amputated bones implanted with 3 analyzed implants were created and loaded with a normal walking and a forward fall load. The strain adaptive bone remodeling theory was used to predict long-term bone changes around the implants and the periprosthetic bone failure risk was evaluated by the von Mises stress criterion. The results show that the new design provides close to physiological distribution of stresses in the bone and lower bone failure risk for the normal walking as compared to the OPRA and the ISP implants. The bone remodeling simulations did not reveal any overall bone loss around the new design, as opposed to the OPRA and the ISP implants, which induce considerable bone loss in the distal end of the femur. This positive outcome shows that the presented concept has a potential to considerably improve safety of the rehabilitation with the direct fixation implants.     

Serotonin Potentiates Transforming Growth Factor-beta3 Induced Biomechanical Remodeling in Avian Embryonic Atrioventricular Valves

Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1α2) in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT), resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical remodeling of AV cushions during development.     

Measurement of microstructural strain in cortical bone

It is well known that mechanical factors affect bone remodeling such that increased mechanical demand results in net bone formation, whereas decreased demand results in net bone resorption. Current theories suggest that bone modeling and remodeling is controlled at the cellular level through signals mediated by osteocytes. The objective of this study was to investigate how macroscopically applied bone strains similar in magnitude to those that occur in vivo are manifest at the microscopic level in the bone matrix. Using a digital image correlation strain measurement technique, experimentally determined bone matrix strains around osteocyte lacuna resulting from macroscopic strains of approximately 2,000 microstrain (0.2%) reach levels of over 30,000 microstrain (3%) over fifteen times greater than the applied macroscopic strain. Strain patterns were highly heterogeneous and in some locations similar to observed microdamage around osteocyte lacuna indicating the resulting strains may represent the precursors to microdamage. This information may lead to a better understanding of how bone cells are affected by whole bone functional loading.     

Cardiac matrix remodeling following intracoronary cell transplantation in dilated cardiomyopathic rabbits

Cellular cardiomyoplasty has been proposed as a promising therapeutic strategy for chronic heart failure. Previous studies focused on structural changes in cardiomyocytes to explain the potential benefits for contractile function. However, limited information is available about the cardiac matrix remodeling following cell transplantation in dilated cardiomyopathy (DCM). Here, we established a new animal model of intracoronary bone marrow mononuclear cells (BMMNCs) transplantation to explore extracellular matrix remodeling in adriamycin-induced cardiomyopathic rabbits. In vivo studies demonstrated that BMMNCs transplantation can dramatically delay the progress of collagen metabolism and decrease myocardial collagen volume fraction. The beneficial effects were mediated by attenuating stress-generated over-expression of matrix metalloproteinases (MMPs) in ventricular remodeling. Improved cardiac function may be contributed in part by stem-associated inhibition of extracellular matrix remodeling.