Abstract. OBJECTIVE. Changes in subchondral bone are one of few disease characteristics to correlate with pain in OA. 1. Profound neuroplasticity and nociceptor sprouting is displayed within osteoarthritic (OA) subchondral bone and is associated with pain and pathology. 2. The cause of these neural changes remains unestablished. Correct innervation patterns are indispensable for bone growth, homeostasis, and repair. Axon guidance signalling factor, Sema3A is essential for the correct innervation patterning of bony tissues. 3. , expressed in osteocytes. 4. and known to be downregulated in bone OA
Degeneration of the intervertebral disc results in patent cracks [1] and a decrease in osmotic pressure associated with loss of fixed charges. The relationship between
Summary Statement. An organ culture experiment was simulated to explore the mechanisms that can link cell death to mechanical overload in the intervertebral disc. Coupling cell nutrition and tissue deformations led to altered metabolic transport that largely explained cell viability measurements. Introduction. Part of intervertebral disc (IVD) maintenance relies on limited nutrient availability to the cells and on
The skeletal system exhibits functional adaptation. For bone the mechanotransduction mechanisms have been well elucidated; in contrast, the response of tendon to its mechanical environment is much more poorly understood despite tendon disorders being commonly encountered in clinical practice. This study presents a novel approach to developing an isolated tendon system in vivo. This model is used to test the hypothesis that stress-shielding, and subsequent restressing, causes significant biomechanical changes. We propose a control mechanism that governs this process. A custom-built external fixator was used to functionally isolate the ovine patellar tendon(PT). In group 1 animals(n=5) the right PT was stress-shielded for 6 weeks. This was achieved by drawing the patella towards the tibial tubercle, thus slackening the PT. In group 2 (n=5) the PT was stress-shielded for 6 weeks. The external fixator was then removed and the PT physiologically loaded for a further 6 weeks. In each case, the PT subsequently underwent tensile testing and measurement of length(L) and cross-sectional area(CSA). The untreated left PTs acted as controls (n=10). 6 weeks of stress-shielding significantly decreased material and structural properties of tendon compared to controls (elastic modulus(E) 76.2%, ultimate tensile strength(UTS) 69.3%, stiffness(S) 79.2%, ultimate load(UL) 68.5%, strain energy(SE) 60.7%; p<
0.05). Ultimate strain(US), L and CSA were not significantly changed. 6 weeks of subsequent functional loading (Group 2) caused some improvement in material properties, but greater recovery in structural properties (E 79.8%, UTS 91.8%, S 96.7%, UL 92.7%, SE 96.5%). CSA was significantly greater than Group 1 tendons at 114% of control value. Previous models of tendon remodelling have relied on either joint immobilization or direct surgical procedures. This model allows close control of the tendon’s mechanical environment whilst allowing normal joint movement and avoiding surgical insult to the tendon itself. The hypothesis that stress-shielding, and subsequent restressing, causes significant biomechanical changes has been upheld. We propose that the biomechanical changes observed are governed by a strain homeostasis feedback mechanism.
Introduction.
Osteoarthritis (OA) is a common cause of chronic pain. Subchondral bone is highly innervated, and bone structural changes directly correlate with pain in OA. Mechanisms underlying skeletal–neural interactions are under-investigated. Bone derived axon guidance molecules are known to regulate bone remodelling. Such signals in the nervous system regulate neural plasticity, branching and neural inflammation. Perturbation of these signals during OA disease progression may disrupt sensory afferents activity, affecting tissue integrity, nociception, and proprioception. Osteocyte
Abstract. Objectives. Prediction of bone adaptation in response to
Stimulation of the mechanosensitive ion channel, Piezo1 promotes bone anabolism and SNPs in the Piezo1 locus are associated with changes in fracture risk. Osteocytes function as critical regulators of bone homeostasis by sensing mechanical signals. The current study used a human, cell-based physiological, 3D in vitro model of bone to determine whether loading of osteocytes in vitro results in upregulation of the Piezo1 pathway. Human Y201 MSCs, embedded in type I collagen gels and differentiated to osteocytes for 7-days, were subjected to pathophysiological load (5000 µstrain, 10Hz, 5 mins; n=6) with unloaded cells as controls (n=4). RNA was extracted 1-hr post load and assessed by RNAseq analysis. To mimic
Abstract. Objectives. The aim of this study was to investigate whether
Abstract. INTRODUCTION. The mechanisms underlying abnormal joint mechanics are poorly understood despite it being a major risk factor for developing osteoarthritis. Glutamate signalling has been implicated in osteoarthritic bone changes and AMPA/kainate glutamate receptor (GluR) antagonists alleviate degeneration in rodent models of osteoarthritis. We investigated whether glutamate signalling molecules are mechanically regulated in a human, cell-based 3D model of bone. METHODS. Human Y201 MSC cells embedded in 3D type I collagen gels (0.05 × 106 cell/gel) differentiated to osteocytes were mechanically loaded in silicone plates (5000 µstrain, 10Hz, 3000 cycles) or not loaded (n=5/group). RNA extracted 1-hr post load was quantified by RTqPCR and RNAseq whole transcriptome analysis (NovaSeq S1 flow cell 2 × 100bp PE reads). Differentially expressed GluRs and glutamate transporters (GluTs) were identified using DEseq2 analysis on normalised count data. Genes were considered differentially expressed if >2 fold change and FDR p<0.05. RESULTS. Cells expressed mature osteocyte markers (E11, sclerostin, DMP-1). DEseq2 analysis, revealed 981 mechanically regulated genes.
In a healthy joint,
It is well known that environmental cues such as
Abstract. Objectives. The mechanisms underlying abnormal joint mechanics are poorly understood despite it being a major risk factor for developing osteoarthritis. This study investigated the response of a 3D in vitro bone cell model to
Abstract. Objectives. Unicompartmental and total knee arthroplasty (UKA and TKA) are successful treatments for osteoarthritis, but monolithic implants disrupt the natural homeostasis of bone which leads to bone loss over time. This can cause problems if the implant needs to be revised. This study aimed to demonstrate that tibial implants made from titanium lattice could replace the tibial condyle surface while minimising disruption of the bone's natural
Abstract. Objectives. Osteocytes function as critical regulators of bone homeostasis by sensing mechanical signals. Stimulation of the mechanosensitive ion channel, Piezo1 promotes bone anabolism and deletion of Piezo1 in osteoblasts and osteocytes decreases bone mass and bone strength in mice. This study determined whether loading of osteocytes in vitro results in upregulation of the Piezo1 pathway. Methods. Human MSC cells (Y201), embedded in type I collagen gels and differentiated to osteocytes in osteogenic media for 7-days, were subjected to pathophysiological load (5000 µstrain, 10Hz, 5 mins; n=6) with unloaded cells as controls (n=4). RNA was extracted 1-hr post load and Piezo1 activation assessed by RNAseq analysis (NovaSeq S1 flow cell 2 × 100bp PE reads). To mimic
Osteoarthritis (OA) is the most common joint disease, which is characterized by a progressive loss of proteoglycans and the destruction of extracellular matrix (ECM), leading to a loss of cartilage integrity and joint function. During OA development, chondrocytes alter ECM synthesis and change their gene expression profile including upregulation of hypertrophic markers known from the growth plate. Although physiological
Tendinopathy is a disease associated with pain and tendon degeneration, leading to a decreased range of motion and an increased risk of tendon rupture. The etiology of this frequent disease is still unknown. In other musculoskeletal tissues like cartilage and intervertebral discs, transient receptor potential channels (TRP- channels) were shown to play a major role in the progression of degeneration. Due to their responsiveness to a wide range of stimuli like temperature, pH, osmolarity and
Articulating cartilage experiences a multitude of biophysical cues. Due to its primary function in distributing load with near frictionless articulation, it is clear that a major stimulus for cartilage homeostasis and regeneration is the