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  1. Article ; Online: Stable Sulforaphane Targets the Early Stages of Osteoclast Formation to Engender a Lasting Functional Blockade of Osteoclastogenesis.

    Louka, Polymnia / Orriss, Isabel R / Pitsillides, Andrew A

    Cells

    2024  Volume 13, Issue 2

    Abstract: Sulforaphane, the native but unstable form of SFX-01, is an antioxidant that activates the NRF2 and inhibits the NF-KB pathways to achieve its actions. Resolving the mechanism(s) by which SFX-01 serves to control the various osteoclastogenic stages may ... ...

    Abstract Sulforaphane, the native but unstable form of SFX-01, is an antioxidant that activates the NRF2 and inhibits the NF-KB pathways to achieve its actions. Resolving the mechanism(s) by which SFX-01 serves to control the various osteoclastogenic stages may expose pathways that could be explored for therapeutic use. Here we seek to identify the stage of osteoclastogenesis targeted by SFX-01 and explore whether, like SFN, it exerts its actions via the NRF2 and NF-KB pathways. Osteoclasts generated from the bone marrow (BM) of mice were cultured with SFX-01 at different timepoints to examine each phase of osteoclastogenesis separately. This showed that SFX-01 exerted actions throughout the process of osteoclastogenesis, but had its largest effects in the early osteoclast precursor differentiation stage. Thus, treatment with SFX-01 for the duration of culture, for the initial 3 days differentiation or for as little as the first 24 h was sufficient for effective inhibition. This aligned with data suggesting that SFX-01 reduced DC-STAMP levels, osteoclast nuclear number and modified cytoskeletal architecture. Pharmacological regulation of the NRF2 pathways, via selective inhibitors/activators, supported the anti-osteoclastogenic roles of an SFX-01-mediated by NRF2 activation, as well as the need for tight NF-KB pathway regulation in osteoclast formation/function.
    MeSH term(s) Animals ; Mice ; Osteoclasts ; Osteogenesis ; NF-E2-Related Factor 2 ; NF-kappa B ; Sulfoxides ; Isothiocyanates
    Chemical Substances sulforaphane (GA49J4310U) ; NF-E2-Related Factor 2 ; NF-kappa B ; Sulfoxides ; Isothiocyanates
    Language English
    Publishing date 2024-01-16
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells13020165
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Keep your Sox on, chondrocytes!

    Pitsillides, Andrew A / Beier, Frank

    Nature reviews. Rheumatology

    2021  Volume 17, Issue 7, Page(s) 383–384

    MeSH term(s) Cell Differentiation ; Chondrocytes ; Humans
    Language English
    Publishing date 2021-05-05
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2491532-4
    ISSN 1759-4804 ; 1759-4790
    ISSN (online) 1759-4804
    ISSN 1759-4790
    DOI 10.1038/s41584-021-00628-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Structural clues to articular calcified cartilage function: A descriptive review of this crucial interface tissue.

    Evans, Lucinda A E / Pitsillides, Andrew A

    Journal of anatomy

    2022  Volume 241, Issue 4, Page(s) 875–895

    Abstract: Articular calcified cartilage (ACC) has been dismissed, by some, as a remnant of endochondral ossification without functional relevance to joint articulation or weight-bearing. Recent research indicates that morphologic and metabolic ACC features may be ... ...

    Abstract Articular calcified cartilage (ACC) has been dismissed, by some, as a remnant of endochondral ossification without functional relevance to joint articulation or weight-bearing. Recent research indicates that morphologic and metabolic ACC features may be important, reflecting knee joint osteoarthritis (OA) predisposition. ACC is less investigated than neighbouring joint tissues, with its component chondrocytes and mineralised matrix often being either ignored or integrated into analyses of hyaline articular cartilage and subchondral bone tissue respectively. Anatomical variation in ACC is recognised between species, individuals and age groups, but the selective pressures underlying this variation are unknown. Consequently, optimal ACC biomechanical features are also unknown as are any potential locomotory roles. This review collates descriptions of ACC anatomy and biology in health and disease, with a view to revealing its structure/function relationship and highlighting potential future research avenues. Mouse models of healthy and OA joint ageing have shown disparities in ACC load-induced deformations at the knee joint. This raises the hypothesis that ACC response to locomotor forces over time may influence, or even underlie, the bony and hyaline cartilage symptoms characteristic of OA. To effectively investigate the ACC, greater resolution of joint imaging and merging of hierarchical scale data will be required. An appreciation of OA as a 'whole joint disease' is expanding, as is the possibility that the ACC may be a key player in healthy ageing and in the transition to OA joint pathology.
    MeSH term(s) Animals ; Cartilage, Articular/pathology ; Chondrocytes/pathology ; Hyaline Cartilage/pathology ; Knee Joint/pathology ; Mice ; Osteoarthritis/pathology
    Language English
    Publishing date 2022-07-22
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2955-5
    ISSN 1469-7580 ; 0021-8782
    ISSN (online) 1469-7580
    ISSN 0021-8782
    DOI 10.1111/joa.13728
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Bone marrow lesions: plugging the holes in our knowledge using animal models.

    Hansen, Rebecca T / Chenu, Chantal / Sofat, Nidhi / Pitsillides, Andrew A

    Nature reviews. Rheumatology

    2023  Volume 19, Issue 7, Page(s) 429–445

    Abstract: Bone marrow lesions (BMLs), which are early signs of osteoarthritis (OA) that are associated with the presence, onset and severity of pain, represent an emerging imaging biomarker and clinical target. Little is known, however, regarding their early ... ...

    Abstract Bone marrow lesions (BMLs), which are early signs of osteoarthritis (OA) that are associated with the presence, onset and severity of pain, represent an emerging imaging biomarker and clinical target. Little is known, however, regarding their early spatial and temporal development, structural relationships or aetiopathogenesis, because of the sparsity of human early OA imaging and paucity of relevant tissue samples. The use of animal models is a logical approach to fill the gaps in our knowledge, and it can be informed by appraising models in which BMLs and closely related subchondral cysts have already been reported, including in spontaneous OA and pain models. The utility of these models in OA research, their relevance to clinical BMLs and practical considerations for their optimal deployment can also inform medical and veterinary clinicians and researchers alike.
    MeSH term(s) Humans ; Animals ; Bone Marrow/pathology ; Osteoarthritis, Knee/diagnosis ; Magnetic Resonance Imaging/methods ; Pain ; Models, Animal
    Language English
    Publishing date 2023-05-24
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2491532-4
    ISSN 1759-4804 ; 1759-4790
    ISSN (online) 1759-4804
    ISSN 1759-4790
    DOI 10.1038/s41584-023-00971-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Moving Beyond the Limits of Detection: The Past, the Present, and the Future of Diagnostic Imaging in Canine Osteoarthritis.

    Jones, Gareth M C / Pitsillides, Andrew A / Meeson, Richard L

    Frontiers in veterinary science

    2022  Volume 9, Page(s) 789898

    Abstract: Osteoarthritis (OA) is the most common orthopedic condition in dogs, characterized as the chronic, painful end-point of a synovial joint with limited therapeutic options other than palliative pain control or surgical salvage. Since the 1970s, radiography ...

    Abstract Osteoarthritis (OA) is the most common orthopedic condition in dogs, characterized as the chronic, painful end-point of a synovial joint with limited therapeutic options other than palliative pain control or surgical salvage. Since the 1970s, radiography has been the standard-of-care for the imaging diagnosis of OA, despite its known limitations. As newer technologies have been developed, the limits of detection have lowered, allowing for the identification of earlier stages of OA. Identification of OA at a stage where it is potentially reversible still remains elusive, however, yet there is hope that newer technologies may be able to close this gap. In this article, we review the changes in the imaging of canine OA over the past 50 years and give a speculative view on future innovations which may provide for earlier identification, with the ultimate goal of repositioning the limit of detection to cross the threshold of this potentially reversible disease.
    Language English
    Publishing date 2022-03-15
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2834243-4
    ISSN 2297-1769
    ISSN 2297-1769
    DOI 10.3389/fvets.2022.789898
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: High bone mass in mice can be linked to lower osteoclast formation, resorptive capacity, and restricted in vitro sensitivity to inhibition by stable sulforaphane.

    Louka, Polymnia / Orriss, Isabel R / Pitsillides, Andrew A

    Cell biochemistry and function

    2022  Volume 40, Issue 7, Page(s) 683–693

    Abstract: Mouse strains can have divergent basal bone mass, yet this phenotype is seldom reflected in the design of studies seeking to identify new modulators of bone resorption by osteoclasts. Sulforaphane exerts inhibitory effects on in vitro osteoclastogenesis ... ...

    Abstract Mouse strains can have divergent basal bone mass, yet this phenotype is seldom reflected in the design of studies seeking to identify new modulators of bone resorption by osteoclasts. Sulforaphane exerts inhibitory effects on in vitro osteoclastogenesis in cells from C57BL/6 mice. Here, we explore whether a divergent basal bone mass in different mouse strains is linked both to in vitro osteoclastogenic potential and to SFX-01 sensitivity. Accordingly, osteoclasts isolated from the bone marrow (BM) of C57BL/6, STR/Ort and CBA mice with low, high, and intermediate bone mass, respectively, were cultured under conditions to promote osteoclast differentiation and resorption; they were also treated with chemically stabilised sulforaphane (SFX-01) and respective sensitivity to inhibition evaluated by counting osteoclast number/resorption activity on dentine discs. We observed that osteoclastogenesis exhibited different macrophage colony-stimulating factor/receptor activator of nuclear factor kappa-Β ligand sensitivity in these mouse strains, with cells from C57BL/6 and CBA generating higher osteoclast numbers than STR/Ort; the latter formed only half as many mature osteoclasts. We found that 100 nM SFX-01 exerted a potent and significant reduction in osteoclast number and resorptive activity in cells derived from C57BL/6 mice. In contrast, 10-fold higher SFX-01 concentrations were required for similar inhibition in CBA-derived cells and, strikingly, a further 2.5-fold greater concentration was required for significant restriction of osteoclast formation/function in STR/Ort. These data are consistent with the notion that the BM osteoclast precursor population contributes to the relative differences in mouse bone mass and that mice with higher bone mass exhibit lower in vitro osteoclastogenic potential as well as reduced sensitivity to inhibition by SFX-01.
    MeSH term(s) Animals ; Bone Resorption/drug therapy ; Cell Differentiation ; Cells, Cultured ; Isothiocyanates ; Ligands ; Macrophage Colony-Stimulating Factor ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Osteoclasts ; RANK Ligand/pharmacology ; Sulfoxides
    Chemical Substances Isothiocyanates ; Ligands ; RANK Ligand ; Sulfoxides ; Macrophage Colony-Stimulating Factor (81627-83-0) ; sulforaphane (GA49J4310U)
    Language English
    Publishing date 2022-08-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 283643-9
    ISSN 1099-0844 ; 0263-6484
    ISSN (online) 1099-0844
    ISSN 0263-6484
    DOI 10.1002/cbf.3734
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: 3D profiling of mouse epiphyses across ages reveals new potential imaging biomarkers of early spontaneous osteoarthritis.

    Herbst, Eva C / Evans, Lucinda A E / Felder, Alessandro A / Javaheri, Behzad / Pitsillides, Andrew A

    Journal of anatomy

    2023  Volume 242, Issue 6, Page(s) 1037–1050

    Abstract: Worldwide research groups and funding bodies have highlighted the need for imaging biomarkers to predict osteoarthritis (OA) progression and treatment effectiveness. Changes in trabecular architecture, which can be detected with non-destructive high- ... ...

    Abstract Worldwide research groups and funding bodies have highlighted the need for imaging biomarkers to predict osteoarthritis (OA) progression and treatment effectiveness. Changes in trabecular architecture, which can be detected with non-destructive high-resolution CT imaging, may reveal OA progression before apparent articular surface damage. Here, we analysed the tibial epiphyses of STR/Ort (OA-prone) and CBA (healthy, parental control) mice at different ages to characterise the effects of mouse age and strain on multiple bony parameters. We isolated epiphyseal components using a semi-automated method, and measured the total epiphyseal volume; cortical bone, trabecular bone and marrow space volumes; mean trabecular and cortical bone thicknesses; trabecular volume relative to cortical volume; trabecular volume relative to epiphyseal interior (trabecular BV/TV); and the trabecular degree of anisotropy. Using two-way ANOVA (significance level ≤0.05), we confirmed that all of these parameters change significantly with age, and that the two strains were significantly different in cortical and trabecular bone volumes, and trabecular degree of anisotropy. STR/Ort mice had higher cortical and trabecular volumes and a lower degree of anisotropy. As the two mouse strains reflect markedly divergent OA predispositions, these parameters have potential as bioimaging markers to monitor OA susceptibility and progression. Additionally, significant age/strain interaction effects were identified for total epiphyseal volume, marrow space volume and trabecular BV/TV. These interactions confirm that the two mouse strains have different epiphyseal growth patterns throughout life, some of which emerge prior to OA onset. Our findings not only propose valuable imaging biomarkers of OA, but also provide insight into ageing 3D epiphyseal architecture bone profiles and skeletal biology underlying the onset and development of age-related OA in STR/Ort mice.
    MeSH term(s) Mice ; Animals ; Mice, Inbred CBA ; Osteoarthritis/diagnostic imaging ; Tibia/diagnostic imaging ; Biomarkers ; Epiphyses/diagnostic imaging
    Chemical Substances Biomarkers
    Language English
    Publishing date 2023-02-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2955-5
    ISSN 1469-7580 ; 0021-8782
    ISSN (online) 1469-7580
    ISSN 0021-8782
    DOI 10.1111/joa.13834
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Resolving trabecular metaphyseal bone profiles downstream of the growth plate adds value to bone histomorphometry in mouse models.

    Salmon, P L / Monzem, S / Javaheri, B / Oste, L / Kerckhofs, G / Pitsillides, A A

    Frontiers in endocrinology

    2023  Volume 14, Page(s) 1158099

    Abstract: Introduction: Histomorphometry of rodent metaphyseal trabecular bone, by histology or microCT, is generally restricted to the mature secondary spongiosa, excluding the primary spongiosa nearest the growth plate by imposing an 'offset'. This analyses the ...

    Abstract Introduction: Histomorphometry of rodent metaphyseal trabecular bone, by histology or microCT, is generally restricted to the mature secondary spongiosa, excluding the primary spongiosa nearest the growth plate by imposing an 'offset'. This analyses the bulk static properties of a defined segment of secondary spongiosa, usually regardless of proximity to the growth plate. Here we assess the value of trabecular morphometry that is spatially resolved according to the distance 'downstream' of-and thus time since formation at-the growth plate. Pursuant to this, we also investigate the validity of including mixed primary-secondary spongiosal trabecular bone, extending the analysed volume 'upstream' by reducing the offset. Both the addition of spatiotemporal resolution and the extension of the analysed volume have potential to enhance the sensitivity of detection of trabecular changes and to resolve changes occurring at different times and locations.
    Method: Two experimental mouse studies of trabecular bone are used as examples of different factors influencing metaphyseal trabecular bone: (1) ovariectomy (OVX) and pharmacological prevention of osteopenia and (2) limb disuse induced by sciatic neurectomy (SN). In a third study into offset rescaling, we also examine the relationship between age, tibia length, and primary spongiosal thickness.
    Results: Bone changes induced by either OVX or SN that were early or weak and marginal were more pronounced in the mixed primary-secondary upstream spongiosal region than in the downstream secondary spongiosa. A spatially resolved evaluation of the entire trabecular region found that significant differences between experimental and control bones remained undiminished either right up to or to within 100 μm from the growth plate. Intriguingly, our data revealed a remarkably linear downstream profile for fractal dimension in trabecular bone, arguing for an underlying homogeneity of the (re)modelling process throughout the entire metaphysis and against strict anatomical categorization into primary and secondary spongiosal regions. Finally, we find that a correlation between tibia length and primary spongiosal depth is well conserved except in very early and late life.
    Conclusions: These data indicate that the spatially resolved analysis of metaphyseal trabecular bone at different distances from the growth plate and/or times since formation adds a valuable dimension to histomorphometric analysis. They also question any rationale for rejecting primary spongiosal bone, in principle, from metaphyseal trabecular morphometry.
    MeSH term(s) Rats ; Female ; Mice ; Animals ; Growth Plate ; Rats, Sprague-Dawley ; Tibia/diagnostic imaging ; Tibia/pathology ; Bone and Bones ; Bone Diseases, Metabolic/pathology ; Disease Models, Animal
    Language English
    Publishing date 2023-03-30
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2023.1158099
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Blood flow restriction training in patients with knee osteoarthritis: Systematic review of randomized controlled trials.

    Pitsillides, Alexios / Stasinopoulos, Dimitrios / Mamais, Ioannis

    Journal of bodywork and movement therapies

    2021  Volume 27, Page(s) 477–486

    Abstract: Introduction: Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders in the elderly. The patient experiences reduction in muscle strength, pain, joint stiffness and consequently a reduction in quality of life. Whereas high ... ...

    Abstract Introduction: Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders in the elderly. The patient experiences reduction in muscle strength, pain, joint stiffness and consequently a reduction in quality of life. Whereas high intensity training (HI-TR) is the most effective in the general elderly population, in KOA patients, painless alternatives might be more suitable, since pain can be a deterrent for exercising. Research interest has increased in blood flow restriction training (BFR-TR) due to the observation that, in this specific population, BFR-TR results in equal muscular adaptions to HI-TR but with less join discomfort/pain.
    Objective: We aimed to: (1) determine the value of BFR-TR in patients with KOA and (2) examine which exercise guidelines applied to healthy elderly populations can be adopted for patients suffering from this knee pathology.
    Methodology: We searched the literature from the database inception to 2019 through PubMed, Cochrane, and Medline (EBSCO). The inclusion criteria were determined using PICOS principles. We assessed methodology using the Risk of Bias 2 tool and the Pedro scale. Conclusions were extracted with the use of best evidence synthesis.
    Results: The literature search yielded 45 articles. After screening, three studies matched the inclusion criteria. The included studies were analyzed and discussed. All the included studies reported within group improvements for BFR-TR regarding pain and strength.
    Conclusion: Although the evidence of BFR-TR efficacy on KOA remains scarce, the results favor its use for muscle strengthening and pain reduction in KOA. Further high-quality studies with larger samples are required.
    MeSH term(s) Aged ; Humans ; Knee Joint ; Muscle Strength ; Osteoarthritis, Knee ; Quality of Life ; Randomized Controlled Trials as Topic ; Regional Blood Flow ; Resistance Training
    Language English
    Publishing date 2021-04-23
    Publishing country United States
    Document type Journal Article ; Review ; Systematic Review
    ZDB-ID 2029441-4
    ISSN 1532-9283 ; 1360-8592
    ISSN (online) 1532-9283
    ISSN 1360-8592
    DOI 10.1016/j.jbmt.2021.04.015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: An evaluation of approaches for rare variant association analyses of binary traits in related samples.

    Chen, Ming-Huei / Pitsillides, Achilleas / Yang, Qiong

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 3145

    Abstract: Recognizing that family data provide unique advantage of identifying rare risk variants in genetic association studies, many cohorts with related samples have gone through whole genome sequencing in large initiatives such as the NHLBI Trans-Omics for ... ...

    Abstract Recognizing that family data provide unique advantage of identifying rare risk variants in genetic association studies, many cohorts with related samples have gone through whole genome sequencing in large initiatives such as the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. Analyzing rare variants poses challenges for binary traits in that some genotype categories may have few or no observed events, causing bias and inflation in commonly used methods. Several methods have recently been proposed to better handle rare variants while accounting for family relationship, but their performances have not been thoroughly evaluated together. Here we compare several existing approaches including SAIGE but not limited to related samples using simulations based on the Framingham Heart Study samples and genotype data from Illumina HumanExome BeadChip where rare variants are the majority. We found that logistic regression with likelihood ratio test applied to related samples was the only approach that did not have inflated type I error rates in both single variant test (SVT) and gene-based tests, followed by Firth logistic regression that had inflation in its direction insensitive gene-based test at prevalence 0.01 only, applied to either related or unrelated samples, though theoretically logistic regression and Firth logistic regression do not account for relatedness in samples. SAIGE had inflation in SVT at prevalence 0.1 or lower and the inflation was eliminated with a minor allele count filter of 5. As for power, there was no approach that outperformed others consistently among all single variant tests and gene-based tests.
    MeSH term(s) Alleles ; Computer Simulation ; Gene Frequency ; Genome, Human ; Genome-Wide Association Study ; Genotype ; Humans ; Logistic Models ; Longitudinal Studies ; Models, Genetic ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; Precision Medicine/methods ; Precision Medicine/statistics & numerical data ; Software
    Language English
    Publishing date 2021-02-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-82547-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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