Nonlinear Stress-Induced Transformations in Collagen Fibrillar Organization, Disorder and Strain Mechanisms in the Bone-Cartilage Unit.

By developing a 3D X-ray modeling and spatially correlative imaging method for fibrous collagenous tissues, this study provides a comprehensive mapping of nanoscale deformation in the collagen fibril network across the intact bone-cartilage unit (BCU), whose healthy functioning is critical for joint function and preventing degeneration. Extracting the 3D fibril structure from 2D small-angle X-ray scattering before and during physiological compression reveals of dominant deformation modes, including crystallinity transitions, lateral fibril compression, and reorientation, which vary in a coupled, nonlinear, and correlated manner across the cartilage-bone interface. A distinct intermolecular arrangement of collagen molecules, and enhanced molecular-level disorder, is found in the cartilage (sliding) surface region.

Air Pollution and Osteoporosis.

Purpose Of Review: The purpose of this review is to provide a background of osteoporosis and air pollution, discussing increasing incidence of the disease with exposure to pollutants and the role that inflammation may play in this process.

Recent Findings: Osteoporosis-related fractures are one of the most pressing challenges for the ageing global population, with significant increases in mortality known to occur after major osteoporotic fractures in the elderly population. Recent studies have established a firm correlative link between areas of high air pollution and increased risk of osteoporosis, particularly alarming given the increasingly urban global population.

A Novel Primary Cilium-Mediated Mechanism Through which Osteocytes Regulate Metastatic Behavior of Both Breast and Prostate Cancer Cells.

Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co-culture, conditioned media, human cancer spheroid, and organ-on-a-chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF-α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88).

Human vascularised synovium-on-a-chip: a mechanically stimulated, microfluidic model to investigate synovial inflammation and monocyte recruitment.

Healthy synovium is critical for joint homeostasis. Synovial inflammation (synovitis) is implicated in the onset, progression and symptomatic presentation of arthritic joint diseases such as rheumatoid arthritis and osteoarthritis. Thus, the synovium is a promising target for the development of novel, disease-modifying therapeutics.

Organ-on-a-Chip and Microfluidic Platforms for Oncology in the UK.

Organ-on-chip systems are capable of replicating complex tissue structures and physiological phenomena. The fine control of biochemical and biomechanical cues within these microphysiological systems provides opportunities for cancer researchers to build complex models of the tumour microenvironment. Interest in applying organ chips to investigate mechanisms such as metastatsis and to test therapeutics has grown rapidly, and this review draws together the published research using these microfluidic platforms to study cancer.

Oscillations of the circadian clock protein, BMAL-1, align to daily cycles of mechanical stimuli: a novel means to integrate biological time within predictive in vitro model systems.

Purpose: In vivo, the circadian clock drives 24-h rhythms in human physiology. Isolated cells in vitro retain a functional clockwork but lack necessary timing cues resulting in the rapid loss of tissue-level circadian rhythms. This study tests the hypothesis that repeated daily mechanical stimulation acts as a timing cue for the circadian clockwork.

Techniques for Visualization and Quantification of Primary Cilia in Chondrocytes.

Primary cilia regulate and coordinate a variety of cell signaling pathways important in chondrocyte physiology and cartilage development, health, and disease. Despite this, the chondrocyte primary cilium and its associated role in cartilage biology remains poorly understood. Key to elucidating primary cilia structure and function in chondrocytes is the ability to visualize this unique structure.

Mechanostimulation of breast myoepithelial cells induces functional changes associated with DCIS progression to invasion.

Women with ductal carcinoma in situ (DCIS) have an increased risk of progression to invasive breast cancer. Although not all women with DCIS will progress to invasion, all are treated as such, emphasising the need to identify prognostic biomarkers. We have previously shown that altered myoepithelial cells in DCIS predict disease progression and recurrence.

Collagen pre-strain discontinuity at the bone-Cartilage interface.

The bone-cartilage unit (BCU) is a universal feature in diarthrodial joints, which is mechanically-graded and subjected to shear and compressive strains. Changes in the BCU have been linked to osteoarthritis (OA) progression. Here we report existence of a physiological internal strain gradient (pre-strain) across the BCU at the ultrastructural scale of the extracellular matrix (ECM) constituents, specifically the collagen fibril.

Reversible changes in the 3D collagen fibril architecture during cyclic loading of healthy and degraded cartilage.

Biomechanical changes to the collagen fibrillar architecture in articular cartilage are believed to play a crucial role in enabling normal joint function. However, experimentally there is little quantitative knowledge about the structural response of the Type II collagen fibrils in cartilage to cyclic loading in situ, and the mechanisms that drive the ability of cartilage to withstand long-term repetitive loading. Here we utilize synchrotron small-angle X-ray scattering (SAXS) combined with in-situ cyclic loading of bovine articular cartilage explants to measure the fibrillar response in deep zone articular cartilage, in terms of orientation, fibrillar strain and inter-fibrillar variability in healthy cartilage and cartilage degraded by exposure to the pro-inflammatory cytokine IL-1β.

Mechanical Stimulation Modulates Osteocyte Regulation of Cancer Cell Phenotype.

Breast and prostate cancers preferentially metastasise to bone tissue, with metastatic lesions forming in the skeletons of most patients. On arriving in bone tissue, disseminated tumour cells enter a mechanical microenvironment that is substantially different to that of the primary tumour and is largely regulated by bone cells. Osteocytes, the most ubiquitous bone cell type, orchestrate healthy bone remodelling in response to physical exercise.

A human multi-cellular model shows how platelets drive production of diseased extracellular matrix and tissue invasion.

Guided by a multi-level "deconstruction" of omental metastases, we developed a tetra (four cell)-culture model of primary human mesothelial cells, fibroblasts, adipocytes, and high-grade serous ovarian cancer (HGSOC) cell lines. This multi-cellular model replicated key elements of human metastases and allowed malignant cell invasion into the artificial omental structure. Prompted by findings in patient biopsies, we used the model to investigate the role of platelets in malignant cell invasion and extracellular matrix, ECM, production.

Modelling TGFβR and Hh pathway regulation of prognostic matrisome molecules in ovarian cancer.

In a multi-level "deconstruction" of omental metastases, we previously identified a prognostic matrisome gene expression signature in high-grade serous ovarian cancer (HGSOC) and twelve other malignancies. Here, our aim was to understand how six of these extracellular matrix (ECM) molecules, COL11A1, cartilage oligomeric matrix protein, FN1, versican, cathepsin B, and COL1A1, are upregulated in cancer. Using biopsies, we identified significant associations between TGFβR activity, Hedgehog (Hh) signaling, and these ECM molecules and studied the associations in mono-, co-, and tri-culture.

Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation.

Primary cilia and associated intraflagellar transport are essential for skeletal development, joint homeostasis, and the response to mechanical stimuli, although the mechanisms remain unclear. Polycystin-2 (PC2) is a member of the transient receptor potential polycystic (TRPP) family of cation channels, and together with Polycystin-1 (PC1), it has been implicated in cilia-mediated mechanotransduction in epithelial cells. The current study investigates the effect of mechanical stimulation on the localization of ciliary polycystins in chondrocytes and tests the hypothesis that they are required in chondrocyte mechanosignaling.

Corrigendum: Mechanical Stimulation: A Crucial Element of Organ-on-Chip Models.

[This corrects the article DOI: 10.3389/fbioe.2020.

Mechanical Stimulation: A Crucial Element of Organ-on-Chip Models.

Organ-on-chip (OOC) systems recapitulate key biological processes and responses exhibited by cells, tissues, and organs . Accordingly, these models of both health and disease hold great promise for improving fundamental research, drug development, personalized medicine, and testing of pharmaceuticals, food substances, pollutants etc. Cells within the body are exposed to biomechanical stimuli, the nature of which is tissue specific and may change with disease or injury.

Solution-Processed Epitaxial Growth of Arbitrary Surface Nanopatterns on Hybrid Perovskite Monocrystalline Thin Films.

Semiconductor surface patterning at the nanometer scale is crucial for high-performance optical, electronic, and photovoltaic devices. To date, surface nanostructures on organic-inorganic single-crystal perovskites have been achieved mainly through destructive methods such as electron-beam lithography and focused ion beam milling. Here, we present a solution-based epitaxial growth method for creating nanopatterns on the surface of perovskite monocrystalline thin films.

Sub-toxic levels of Co are anti-inflammatory and protect cartilage from degradation caused by IL-1β.

Background: Cobalt ions from some orthopaedic implants induce a dose-dependent cytotoxic and pro-inflammatory response. Recent studies show that sub-toxic levels of cobalt influence actin organisation regulating fibroblasts and macrophages behaviour. However little is known about the influence of sub-toxic levels of cobalt on articular cartilage biology and biomechanics.

Nanoscale Mapping Reveals Functional Differences in Ion Channels Populating the Membrane of Primary Cilia.

Background/aims: The primary cilium is a nanoscale membrane protrusion believed to act as a mechano-chemical sensor in a range of different cell types. Disruptions in its structure and signalling have been linked to a number of medical conditions, referred to as ciliopathies, but remain poorly understood due to lack of techniques capable of investigating signal transduction in cilia at nanoscale. Here we set out to use latest advances in nanopipette technology to address the question of ion channel distribution along the structure of primary cilium.

Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model.

The human PKD2 locus encodes Polycystin-2 (PC2), a TRPP channel that localises to several distinct cellular compartments, including the cilium. PKD2 mutations cause Autosomal Dominant Polycystic Kidney Disease (ADPKD) and affect many cellular pathways. Data underlining the importance of ciliary PC2 localisation in preventing PKD are limited because PC2 function is ablated throughout the cell in existing model systems.

Proteoglycan degradation mimics static compression by altering the natural gradients in fibrillar organisation in cartilage.

Structural and associated biomechanical gradients within biological tissues are important for tissue functionality and preventing damaging interfacial stress concentrations. Articular cartilage possesses an inhomogeneous structure throughout its thickness, driving the associated variation in the biomechanical strain profile within the tissue under physiological compressive loading. However, little is known experimentally about the nanostructural mechanical role of the collagen fibrils and how this varies with depth.

An in vitro investigation of the inflammatory response to the strain amplitudes which occur during high frequency oscillation ventilation and conventional mechanical ventilation.

Children randomised in the neonatal period to high frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CMV) in the United Kingdom Oscillation study (UKOS) had superior lung function at 11 to 14 years of age. During HFOV, much smaller tidal volumes, but a higher mean airway distending pressure is delivered, hence, a possible explanation for a volume dependent effect on long term lung function could be an increase in inflammation in response to higher tidal volumes and strains. We tested that hypothesis by assessing interleukin-6 (IL-6) and -8 (IL-8) release from A549 alveolar analogue cells following biaxial mechanical strain applied at 0.

Oncometabolite induced primary cilia loss in pheochromocytoma.

Primary cilia are sensory organelles involved in regulation of cellular signaling. Cilia loss is frequently observed in tumors; yet, the responsible mechanisms and consequences for tumorigenesis remain unclear. We demonstrate that cilia structure and function is disrupted in human pheochromocytomas - endocrine tumors of the adrenal medulla.

Mechanical loading induces primary cilia disassembly in tendon cells via TGFβ and HDAC6.

This study used isolated human tenocytes to test the hypothesis that cyclic mechanical strain directly stimulates primary cilia disassembly, and to elucidate the mechanisms involved. Cells were seeded onto flexible membranes and strained at 0-3%; 1 Hz, for up to 24 hours. Cilia length and prevalence progressively reduced with increasing strain duration but showed full recovery within 2 hours of strain removal.