scholarly journals Suppressed Osteocyte Perilacunar / Canalicular Remodeling Plays a Causal Role in Osteoarthritis

2019 ◽  
Author(s):  
Courtney M. Mazur ◽  
Jonathon J. Woo ◽  
Cristal S. Yee ◽  
Aaron J. Fields ◽  
Claire Acevedo ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Cartilage Degeneration ◽  
Causal Role ◽  
Knee Joints ◽  
Cellular Mechanisms ◽  
Primary Disorder ◽  
End Stage ◽  
Early Oa ◽  
Protease Expression

ABSTRACTOsteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicular remodeling (PLR) was most severe in OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. To determine if PLR suppression plays a causal role in OA, we ablated the PLR enzyme MMP13 in osteocytes, while leaving chondrocytic MMP13 intact. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, this osteocyte-intrinsic PLR defect was sufficient to reduce cartilage proteoglycan content and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, osteocyte PLR is a critical regulator of cartilage homeostasis. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and identify the causal role of suppressed perilacunar/canalicular remodeling in osteoarthritis.

scholarly journals Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis

Bone Research ◽  
2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Courtney M. Mazur ◽  
Jonathon J. Woo ◽  
Cristal S. Yee ◽  
Aaron J. Fields ◽  
Claire Acevedo ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Cartilage Degeneration ◽  
Knee Joints ◽  
Cartilage Defects ◽  
Bone Homeostasis ◽  
Cellular Mechanisms ◽  
Content Change ◽  
Primary Disorder ◽  
End Stage ◽  
Early Oa

Abstract Osteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicular remodeling (PLR) was most severe in the medial compartment of OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. As a step toward evaluating the causality of PLR suppression in OA, we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact, using Cre recombinase driven by the 9.6-kb DMP1 promoter. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content, change chondrocyte production of collagen II, aggrecan, and MMP13, and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, defects in PLR coincide with cartilage defects. Osteocyte-derived MMP13 emerges as a critical regulator of cartilage homeostasis, likely via its effects on PLR. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis.

scholarly journals Cartilage microRNA dysregulation in mouse osteoarthritis overlaps with patient disease candidates

2017 ◽  
Author(s):  
Louise H. W. Kung ◽  
Varshini Ravi ◽  
Lynn Rowley ◽  
Constanza Angelucci ◽  
Amanda J Fosang ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Expression Profiling ◽  
Medial Meniscus ◽  
Global Analysis ◽  
Cartilage Degeneration ◽  
Osteophyte Formation ◽  
Bone Sclerosis ◽  
End Stage ◽  
Microrna Dysregulation

ABSTRACTTo explore the role of microRNAs in osteoarthritis (OA), we conducted microRNA expression profiling on micro-dissected tibial cartilage and subchondral bone in a mouse model of OA produced by medial meniscus destabilization (DMM). DMM mice had characteristic cartilage degeneration, subchondral bone sclerosis and osteophyte formation. While subchondral bone showed no microRNA dysregulation, 139 microRNAs were differentially expressed in DMM cartilage at 1 and/or 6 weeks after OA initiation. To prioritize OA-candidates, dysregulated microRNAs with human orthologues were filtered using paired microRNA:mRNA expression analysis to identify those with corresponding changes in mRNA target transcripts in the DMM cartilage. An important cohort overlapped with microRNAs identified in human end-stage OA. Comparisons with microRNAs dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically-ablated demonstrated that all were independent of aggrecan breakdown, earmarking these as important to the critical stages of OA initiation. Our comprehensive analyses identified high-priority microRNA candidates that have potential as human OA-biomarkers and therapeutic targets.SUMMARYKung et al. conducted global analysis of microRNA dysregulation in joint tissues of a well-established mouse osteoarthritis model. Stringent filtering against human microRNA orthologues, integrated mRNA target analysis and comparison with published studies on human end-stage osteoarthritis identified microRNA candidates of potential clinical relevance.

scholarly journals Subchondral bone microenvironment in osteoarthritis and pain

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Yan Hu ◽  
Xiao Chen ◽  
Sicheng Wang ◽  
Yingying Jing ◽  
Jiacan Su
Keyword(s):  
Subchondral Bone ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Sensory Nerve ◽  
Cartilage Degeneration ◽  
Cartilage Destruction ◽  
Future Research ◽  
Bone Lesions ◽  
Obesity Trends

AbstractOsteoarthritis comprises several joint disorders characterized by articular cartilage degeneration and persistent pain, causing disability and economic burden. The incidence of osteoarthritis is rapidly increasing worldwide due to aging and obesity trends. Basic and clinical research on osteoarthritis has been carried out for decades, but many questions remain unanswered. The exact role of subchondral bone during the initiation and progression osteoarthritis remains unclear. Accumulating evidence shows that subchondral bone lesions, including bone marrow edema and angiogenesis, develop earlier than cartilage degeneration. Clinical interventions targeting subchondral bone have shown therapeutic potential, while others targeting cartilage have yielded disappointing results. Abnormal subchondral bone remodeling, angiogenesis and sensory nerve innervation contribute directly or indirectly to cartilage destruction and pain. This review is about bone-cartilage crosstalk, the subchondral microenvironment and the critical role of both in osteoarthritis progression. It also provides an update on the pathogenesis of and interventions for osteoarthritis and future research targeting subchondral bone.

scholarly journals Sympathetic influences on articular cartilage regeneration capacity and osteoarthritis manifestation

2021 ◽  
Author(s):  
◽  
Karima El Bagdadi
Keyword(s):  
Subchondral Bone ◽  
Adrenergic Receptor ◽  
Cartilage Regeneration ◽  
Cartilage Degeneration ◽  
Bone Changes ◽  
Β2 Adrenergic Receptor ◽  
Deficient Mice

The pathogenesis of osteoarthritis (OA) involves articular cartilage, synovial tissue and subchondral bone and is therefore a disease of the whole joint. OA is characterized by progressive degradation of cartilage, synovial inflammation, osteophyte formation and subchondral bone sclerosis. Cartilage-surrounding tissues are innervated by tyrosine hydroxylase (TH)-positive sympathetic nerve fibers with the most important sympathetic neurotransmitter norepinephrine (NE) detected in the synovial fluid of OA patients. Furthermore, adrenergic receptors are expressed in different knee joint tissues. Most in vitro studies indicate a potential role of the β2-adrenergic receptor, which has been not investigated during OA pathogenesis in vivo. The role of the sympathetic nervous system (SNS) in OA progression has not yet been studied. Therefore, the objective of this study was to analyze how the SNS and NE influence the MSC dependent cartilage regeneration in vitro and the OA pathogenesis and manifestation in vivo. In the first part of this study, the effect of NE on the chondrogenesis of sASC, which are known to play an important role in cartilage regeneration was analyzed in vitro. In the second part of this study, the role of the SNS was studied in vivo in mice that were sympathectomized chemically followed by surgically induced OA. The specific focus was on the β2-adrenergic receptor effects on OA pathogenesis, which were analyzed in β2-adrenergic receptor-deficient mice. The in vitro experiments have shown that NE reduced the chondrogenic potential of sASCs by decreasing the expression of type II collagen and sGAG. NE mediated these effects mainly by the α2-AR signalling. Furthermore, NE treatment led to activation of the ERK1/2 signal pathway. These findings suggested that the sympathetic neurotransmitter NE might suppress the chondrogenic capacity of MSC and their dependent cartilage regeneration and may also play a role in OA progression and manifestation. The in vivo study has shown that sympathectomy reduced synovial TH-positive nerve fibers in the synovium and the NE concentration in the spleen significantly. In WT mice, DMM leads to increased NE concentrations in the spleen compared to sham mice indicating an increased SNS activity after mechanical stress or inflammation due to DMM. Sympathectomy leads to less pronounced cartilage degeneration (OARSI score) after DMM compared to DMM in WT mice. Furthermore, the release of the type II collagen degradation fragment CTX-II was abolished in Syx DMM mice compared to WT DMM mice, suggesting that less SNS activity due to sympathectomy reduced the cartilage degeneration during OA pathogenesis. Similarly, sympathectomy decreased the synovitis score significantly after DMM compared to DMM in WT mice. Synovitis in WT mice was accompanied by increased MMP-13 expression in the synovium after DMM, compared to Syx mice. Cartilage degeneration seemed to be driven mainly by the increased synovial inflammation accompanied by an increased MMP13 expression in synoviocytes and not in chondrocytes. The pathological changes in synovium and cartilage might also be linked to each other, as indicated by the moderate correlation between the synovial inflammation (synovitis score) and cartilage degeneration (OARSI score). Subchondral bone volume as well the thickness of the subchondral bone plate (SCBP) and calcified cartilage (CC) were increased in Syx mice compared to WT after DMM. The data on DMM induction in β2-AR deficient mice revealed that the β2-AR signaling is involved in cartilage degeneration and the aggravated subchondral bone changes as these mice had less pronounced cartilage degeneration compared to WT mice. While the cartilage degeneration was similar, the subchondral bone changes were more pronounced in β2-AR deficient mice compared to the Syx mice. Overall, the SNS had differential effects in cartilage, synovium and subchondral bone. A reduced SNS activity by sympathectomy attenuated cartilage degeneration and synovitis but aggravated the OA specific subchondral bone changes. These findings provide new insights into the development of novel therapeutic strategies for OA by targeting the SNS in a tissue- specific manner.

scholarly journals Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of CCN2

2020 ◽  
Author(s):  
Craig M Keenan ◽  
Lorenzo Ramos-Mucci ◽  
Ioannis Kanakis ◽  
Peter I Milner ◽  
Andrew Leask ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Cartilage Degeneration ◽  
Knee Joints ◽  
Matricellular Protein ◽  
Non Invasive ◽  
Post Surgery ◽  
Surgical Model ◽  
Summary Statement ◽  
Post Traumatic

AbstractCCN2 is a matricellular protein involved in several critical biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. CCN2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development, however its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). CCN2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-CT, and processed for histology. Sections were stained with toluidine blue and scored using the OARSI grading system. In the non-invasive model cartilage lesions were present in the lateral femur but no significant differences were observed between wildtype (WT) and CCN2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments but no significant differences were observed between WT and CCN2 KO mice at 2, 4, and 8 weeks post-surgery. We conclude that CCN2 deletion in chondrocytes did not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a critical player in protecting cartilage from the degeneration associated with PTOA.Summary StatementPost-natal deletion of CCN2 in chondrocytes does not affect the development of post-traumatic osteoarthritis in mice.

scholarly journals Developmental Transformation and Reduction of Connective Cavities within the Subchondral Bone

2019 ◽  
Vol 20 (3) ◽  
pp. 770 ◽  
Author(s):  
Shahed Taheri ◽  
Thomas Winkler ◽  
Lia Schenk ◽  
Carl Neuerburg ◽  
Sebastian Baumbach ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Volume Fraction ◽  
Early Adulthood ◽  
Sample Type ◽  
Bone Volume Fraction ◽  
Medial Condyle ◽  
Calcified Cartilage ◽  
Degree Of Anisotropy ◽  
Early Oa

It is widely accepted that the subchondral bone (SCB) plays a crucial role in the physiopathology of osteoarthritis (OA), although its contribution is still debated. Much of the pre-clinical research on the role of SCB is concentrated on comparative evaluations of healthy vs. early OA or early OA vs. advanced OA cases, while neglecting how pure maturation could change the SCB’s microstructure. To assess the transformations of the healthy SCB from young age to early adulthood, we examined the microstructure and material composition of the medial condyle of the femur in calves (three months) and cattle (18 months) for the calcified cartilage (CC) and the subchondral bone plate (SCBP). The entire subchondral zone (SCZ) was significantly thicker in cattle compared to calves, although the proportion of the CC and SCBP thicknesses were relatively constant. The trabecular number (Tb.N.) and the connectivity density (Conn.D) were significantly higher in the deeper region of the SCZ, while the bone volume fraction (BV/TV), and the degree of anisotropy (DA) were more affected by age rather than the region. The mineralization increased within the first 250 µm of the SCZ irrespective of sample type, and became stable thereafter. Cattle exhibited higher mineralization than calves at all depths, with a mean Ca/P ratio of 1.59 and 1.64 for calves and cattle, respectively. Collectively, these results indicate that the SCZ is highly dynamic at early age, and CC is the most dynamic layer of the SCZ.

Do Writing Directions Influence How People Map Space onto Time?

2018 ◽  
Vol 77 (4) ◽  
pp. 173-184
Author(s):  
Wenxing Yang ◽  
Ying Sun
Keyword(s):  
Mental Representations ◽  
Space Time ◽  
Horizontal Axis ◽  
Causal Role ◽  
Writing Systems ◽  
Temporal Cognition ◽  
Japanese Speakers ◽  
Psychological Experiments ◽  
Vertical Up

Abstract. The causal role of a unidirectional orthography in shaping speakers’ mental representations of time seems to be well established by many psychological experiments. However, the question of whether bidirectional writing systems in some languages can also produce such an impact on temporal cognition remains unresolved. To address this issue, the present study focused on Japanese and Taiwanese, both of which have a similar mix of texts written horizontally from left to right (HLR) and vertically from top to bottom (VTB). Two experiments were performed which recruited Japanese and Taiwanese speakers as participants. Experiment 1 used an explicit temporal arrangement design, and Experiment 2 measured implicit space-time associations in participants along the horizontal (left/right) and the vertical (up/down) axis. Converging evidence gathered from the two experiments demonstrate that neither Japanese speakers nor Taiwanese speakers aligned their vertical representations of time with the VTB writing orientation. Along the horizontal axis, only Japanese speakers encoded elapsing time into a left-to-right linear layout, which was commensurate with the HLR writing direction. Therefore, two distinct writing orientations of a language could not bring about two coexisting mental time lines. Possible theoretical implications underlying the findings are discussed.

MOLECULAR ASPECTS OF SARCOPENIA PATHOGENESIS IN CHRONOC KIDNEY DISEASE: INTEGRATED ROLE OF mTOR

2018 ◽  
Vol 22 (5) ◽  
pp. 9-16 ◽  
Author(s):  
M. Z. Gasanov
Keyword(s):  
Kidney Disease ◽  
Muscle Mass ◽  
Protein Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Healthy Person ◽  
Scientific Review ◽  
Cytoskeleton Organization ◽  
Molecular Aspects ◽  
End Stage

In recent decades, the main pathogenetic mechanisms for maintaining muscle mass and strength have been discovered. Most of the scientific papers on the molecular aspects of the  pathogenesis of sarcopenia were focused on the Akt-signaling  pathway. The subject of the study were people of elderly and senile  age, immobilized patients, patients with CKD 1-4 stages, animals. However, recently more attention has been paid to the role  of protein – the mammalian target of rapamycin mTOR. It seems to be a key link in the control of muscle mass and is a promising  marker in understanding the mechanisms of the pathogenesis of  sarcopenia. Its importance in protein metabolism in patients with  end stage kidney disease is not studied and requires further research. The presented scientific review contains  information on the role of mTOR and its components – mTORC1 and mTORC2 in maintaining muscle mass and strength in a healthy  person and in the formation of sarcopenia in patients with CKD. The  general aid of mTORC1 complex is regulation of protein production  which is necessary for cell growth and differentiation. mTORC2  complex functions are not enough studied. It is established that it  plays important role in such biological processes as cytoskeleton  organization, intracellular homeostasis maintaining, so it provides  cell resistance and cell survivability in negative external and internal  impulses. mTOR protein can be considered as promising molecular  marker in diagnostics of protein metabolism early disturbances in  patients with CKD and also as additory factor of sarcopenia severity assessment.

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