Pathophysiology of periarticular bone changes in osteoarthritis

2016 ◽  
Author(s):  
Steven R. Goldring
Keyword(s):  
Bone Cells ◽  
Mechanical Load ◽  
Bone Pathology ◽  
Cellular Mechanisms ◽  
Physiological Conditions ◽  
Cellular Processes ◽  
Composition And Structure ◽  
Structural And Functional Properties ◽  
Diarthrodial Joints ◽  
Bone Changes

Under physiological conditions, the subchondral bone of diarthrodial joints such as the hip, knee, and phalanges forms an integrated biocomposite with the overlying calcified and hyaline articular cartilage that is optimally organized to transfer mechanical load. During the evolution of the osteoarthritic process both the periarticular bone and cartilage undergo marked changes in their structural and functional properties in response to adverse biomechanical and biological signals. These changes are mediated by bone cells that modify the architecture and properties of the bone through active cellular processes of modelling and remodelling. These same biomechanical and biological factors also affect chondrocytes in the cartilage matrix altering the composition and structure of the cartilage and further disrupting the homeostatic relationship between the cartilage and bone. This chapter reviews the structural alterations and cellular mechanisms involved in the pathogenesis of osteoarthritis bone pathology and discusses potential approaches for targeting bone remodelling to attenuate the progression of the osteoarthritic process.

scholarly journals Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2474
Author(s):  
Lyudmila V. Gromova ◽  
Serguei O. Fetissov ◽  
Andrey A. Gruzdkov
Keyword(s):  
Small Intestine ◽  
Blood Glucose ◽  
Metabolic Diseases ◽  
Glucose Absorption ◽  
Cellular Mechanisms ◽  
Physiological Conditions ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
New Strategy ◽  
Intestinal Glucose Absorption

The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.

scholarly journals Maternal Uterine Vascular Remodeling During Pregnancy

Physiology ◽  
2009 ◽  
Vol 24 (1) ◽  
pp. 58-71 ◽  
Author(s):  
George Osol ◽  
Maurizio Mandala
Keyword(s):  
Extracellular Matrix ◽  
Blood Flow ◽  
Vascular Remodeling ◽  
Normal Pregnancy ◽  
Uterine Blood Flow ◽  
Growth And Remodeling ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Uteroplacental Blood Flow ◽  
Uterine Circulation

Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodeling of the entire uterine circulation, as well as the creation of a new fetal vascular organ: the placenta. The process of remodeling involves a number of cellular processes, including hyperplasia and hypertrophy, rearrangement of existing elements, and changes in extracellular matrix. In this review, we provide information on uterine blood flow increases during pregnancy, the influence of placentation type on the distribution of uterine vascular resistance, consideration of the patterns, nature, and extent of maternal uterine vascular remodeling during pregnancy, and what is known about the underlying cellular mechanisms.

scholarly journals Effects of uniaxial stretching on tenocyte migration behaviour

2018 ◽  
Vol 4 (1) ◽  
pp. 313-317 ◽  
Author(s):  
Gözde Dursun ◽  
Mersedeh Tohidnezhad ◽  
Bernd Markert ◽  
Marcus Stoffel
Keyword(s):  
Mechanical Load ◽  
Healing Process ◽  
Specific Treatment ◽  
Wound Site ◽  
Cellular Processes ◽  
Unstimulated Control ◽  
Bioreactor System ◽  
Collagen Membranes ◽  
Mechanical Stretching ◽  
Silicone Membranes

AbstractIt is widely known that tendon tissues are subjected to repeated cyclic mechanical load which influences cellular processes. The involvement of principles of mechanics in tissue engineering contributes to the investigations of the connection between mechanical and biological parameters in cellular processes and as well as to the development of new approaches for specific treatment methods. The healing process of injured tendons includes tenocyte migration which occurs from intact regions of tendon into the wound site. The aim of the present study is to investigate and enhance the migration characteristics of tenocytes under uniaxial mechanical stretching using an in-house tensile bioreactor system. Uniaxial mechanical stretching is applied to tenocyte-seeded silicone as well as collagen membranes, which possess different material properties. Tenocyte-seeded silicone membranes were investigated under three different loading conditions, including unstimulated (control), 3% and 5% strain, at frequency of 0.5 Hz. Tenocyte-seeded collagen membranes were investigated using three different frequencies, including unstimulated (control), 0.1 Hz and 0.5 Hz at strain of 4%. The main finding in this study is that uniaxially mechanical stretching at 3% strain enhances the cell migration more than 5% strain on silicone membranes.

scholarly journals E11/gp38 Selective Expression in Osteocytes: Regulation by Mechanical Strain and Role in Dendrite Elongation

2006 ◽  
Vol 26 (12) ◽  
pp. 4539-4552 ◽  
Author(s):  
Keqin Zhang ◽  
Cielo Barragan-Adjemian ◽  
Ling Ye ◽  
Shiva Kotha ◽  
Mark Dallas ◽  
...  
Keyword(s):  
Shear Stress ◽  
Cell Lines ◽  
Mechanical Load ◽  
Mechanical Strain ◽  
Three Dimensional ◽  
Cell Communication ◽  
Bone Surface ◽  
Cellular Processes ◽  
Primary Osteoblasts

ABSTRACT Within mineralized bone, osteocytes form dendritic processes that travel through canaliculi to make contact with other osteocytes and cells on the bone surface. This three-dimensional syncytium is thought to be necessary to maintain viability, cell-to-cell communication, and mechanosensation. E11/gp38 is the earliest osteocyte-selective protein to be expressed as the osteoblast differentiates into an osteoid cell or osteocyte, first appearing on the forming dendritic processes of these cells. Bone extracts contain large amounts of E11, but immunostaining only shows its presence in early osteocytes compared to more deeply embedded cells, suggesting epitope masking by mineral. Freshly isolated primary osteoblasts are negative for E11 expression but begin to express this protein in culture, and expression increases with time, suggesting differentiation into the osteocyte phenotype. Osteoblast-like cell lines 2T3 and Oct-1 also show increased expression of E11 with differentiation and mineralization. E11 is highly expressed in MLO-Y4 osteocyte-like cells compared to osteoblast cell lines and primary osteoblasts. Differentiated, mineralized 2T3 cells and MLO-Y4 cells subjected to fluid flow shear stress show an increase in mRNA for E11. MLO-Y4 cells show an increase in dendricity and elongation of dendrites in response to shear stress that is blocked by small interfering RNA specific to E11. In vivo, E11 expression is also increased by a mechanical load, not only in osteocytes near the bone surface but also in osteocytes more deeply embedded in bone. Maximal expression is observed not in regions of maximal strain but in a region of potential bone remodeling, suggesting that dendrite elongation may be occurring during this process. These data suggest that osteocytes may be able to extend their cellular processes after embedment in mineralized matrix and have implications for osteocytic modification of their microenvironment.

Abstract 497: Cholesterol and Toll-like Receptor Signaling Are Important Regulators of Macrophage Interactions with Atherosclerotic Lipoprotein Aggregates

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Harvey F Chin ◽  
Abigail Haka ◽  
Frederick R Maxfield
Keyword(s):  
Molecular Mechanisms ◽  
Atherosclerotic Plaques ◽  
Cholesteryl Esters ◽  
Cellular Mechanisms ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Atherosclerotic Plaque Formation ◽  
Subendothelial Space ◽  
Morphological Responses ◽  
Cytoskeletal Rearrangements

Macrophages encounter deposits of aggregated low-density lipoproteins (agLDL) in the subendothelial space of blood vessels during the first stages of atherosclerotic plaque formation. Notably, current models for the mechanism of macrophage internalization of cholesterol in early atherosclerotic plaques are incomplete due to the lack of attention paid to the unique cellular mechanisms that are required for macrophages to degrade aggregates of LDL in particular, which can comprise >90% of the LDL in atherosclerotic plaques. In fact, internalization of cholesterol from cholesteryl esters in agLDL involves the development of intriguing cellular processes in which extracellular acidic compartments, lysosomal synapses (LSs), are formed whereby agLDL is partially degraded prior to internalization. This process requires extensive cytoskeletal rearrangements and secretion of lysosomal enzymes responsible for hydrolysis of cholesteryl esters from the agLDL. Subsequent delivery of free cholesterol from agLDL to the macrophage plasma membrane is central for development of the LS. Nonetheless, the molecular mechanism underlying initiation and propagation of the LS are currently largely unknown. This research proposal aims to elucidate the molecular mechanisms of LS formation and the role that cholesterol plays in eliciting these morphological responses to agLDL. Fluorescence microscopy assays were used to identify activation of TLR4 and downstream signaling involving PI3K and Akt as important events leading to LS formation. Furthermore, morphological responses of macrophages to cholesterol overloading require overlapping signaling pathways, indicating the role of interplay of cholesterol and TLR4 signaling in development of this novel macrophage interaction with aggregated LDL found in plaques. Identification of specific molecular pathways involved in this process will not only contribute to the basic understanding of one of the primary cellular processes contributing to atherosclerosis, one of the primary causes of heart disease, but also provide tangible molecular targets for the ultimate development of therapies.

scholarly journals Molecular and Clinical Insights into the Invasive Capacity of Glioblastoma Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Carlos Velásquez ◽  
Sheila Mansouri ◽  
Carla Mora ◽  
Farshad Nassiri ◽  
Suganth Suppiah ◽  
...  
Keyword(s):  
Treatment Resistance ◽  
Host Cells ◽  
Cellular Mechanisms ◽  
Poor Overall Survival ◽  
Cellular Processes ◽  
New Therapeutic Approaches ◽  
Invasive Capacity ◽  
Molecular Machinery ◽  
The Impact ◽  
Infiltrative Tumor

The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.

scholarly journals Tagging the proteasome active site β5 causes tag specific phenotypes in yeast

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kenrick A. Waite ◽  
Alicia Burris ◽  
Jeroen Roelofs
Keyword(s):  
Nitrogen Starvation ◽  
Critical Role ◽  
26S Proteasome ◽  
Core Particle ◽  
Poor Growth ◽  
Physiological Conditions ◽  
Cellular Processes ◽  
Storage Granules ◽  
Fluorescent Tags ◽  
Gfp Tag

Abstract The efficient and timely degradation of proteins is crucial for many cellular processes and to maintain general proteostasis. The proteasome, a complex multisubunit protease, plays a critical role in protein degradation. Therefore, it is important to understand the assembly, regulation, and localization of proteasome complexes in the cell under different conditions. Fluorescent tags are often utilized to study proteasomes. A GFP-tag on the β5 subunit, one of the core particle (CP) subunits with catalytic activity, has been shown to be incorporated into proteasomes and commonly used by the field. We report here that a tag on this subunit results in aberrant phenotypes that are not observed when several other CP subunits are tagged. These phenotypes appear in combination with other proteasome mutations and include poor growth, and, more significantly, altered 26S proteasome localization. In strains defective for autophagy, β5-GFP tagged proteasomes, unlike other CP tags, localize to granules upon nitrogen starvation. These granules are reflective of previously described proteasome storage granules but display unique properties. This suggests proteasomes with a β5-GFP tag are specifically recognized and sequestered depending on physiological conditions. In all, our data indicate the intricacy of tagging proteasomes, and possibly, large complexes in general.

Selected Contribution: Regulatory pathways involved in mechanical induction of c-fos gene expression in bone cells

2000 ◽  
Vol 89 (6) ◽  
pp. 2498-2507 ◽  
Author(s):  
M. A. Peake ◽  
L. M. Cooling ◽  
J. L. Magnay ◽  
P. B. M. Thomas ◽  
A. J. El Haj
Keyword(s):  
Bone Cells ◽  
Mechanical Load ◽  
Mechanical Strain ◽  
Collagen Type I ◽  
Bone Cell ◽  
Type I ◽  
Regulatory Pathways ◽  
Four Point Bending ◽  
Load Response ◽  
Factor C

The regulatory pathways involved in the rapid response of the AP-1 transcription factor, c- fos, to mechanical load in human primary osteoblast-like (HOB) cells and the human MG-63 bone cell line were investigated using a four-point bending model. HOB and MG-63 cells showed upregulation of c- fos expression on fibronectin and collagen type I substrates; however, MG-63 cells did not respond on laminin YIGSR substrates. Addition of cytochalasin D and Arg-Gly-Asp peptides during loading did not inhibit the response, whereas addition of β1-integrin antibodies inhibited the load response. The role of Ca2+ signaling has been demonstrated by blocking upregulation with addition of 2 mM EGTA, which chelates extracellular Ca2+, and gadolinium (10 μM), which inhibits stretch-activated channels. Addition of the Ca2+ ionophore A-23187 induced upregulation without loading; however, addition of nifedipine (10 μM), the L-type channel blocker, failed to prevent the load response. Inhibitors of downstream pathways indicated the involvement of protein kinase C. Our results demonstrate a key involvement of Ca2+ signaling pathways and integrin binding in the c- fos response to mechanical strain.

scholarly journals Colonic Epithelial miR-31 Associates with the Development of Crohn’s Phenotypes

2018 ◽  
Author(s):  
Benjamin P. Keith ◽  
Jasmine B. Barrow ◽  
Takahiko Toyonaga ◽  
Nevzat Kazgan ◽  
Michelle Hoffner O’Connor ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Cell Types ◽  
Adult Patients ◽  
Small Rna Sequencing ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Treatment Naïve ◽  
History Of ◽  
Mucosa Cell ◽  
Ileal Disease

AbstractCrohn’s disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. In this study, small RNA-sequencing and microRNA profiling in the colon revealed two distinct molecular subtypes, each with different clinical associations, in both adult and treatment-naïve pediatric CD patients. Notably, we found that microRNA-31 (miR-31) expression by itself can stratify patients into these two subtypes. Through detailed analysis of several colonic mucosa cell types from adult patients, we found that differential levels of miR-31 are particularly pronounced in epithelial cells. We generated patient crypt-derived epithelial colonoids and showed that miR-31 expression differences preserved in this ex-vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery are associated with post-operative recurrence of ileal disease. In pediatric patients, lower miR-31 expression at the time of diagnosis is associated with the future development of fibrostenotic ileal CD requiring surgery. These findings represent an important step forward in designing more effective clinical trials and developing personalized therapies for CD.

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