Background: The number of people presenting with osteoarthritis is increasing due, largely, to an ageing population and advances in medical treatments. This is driving the demand for new clinical solutions and treatme...Background: The number of people presenting with osteoarthritis is increasing due, largely, to an ageing population and advances in medical treatments. This is driving the demand for new clinical solutions and treatments for the disease. Biologic therapies have been touted as an adjunct, or even alternative to established treatments for osteoarthritis. The term “biologics” refers to protein-based therapeutics that are derived from the proteins of living organisms. These treatments include, but are not limited to: autologous blood products such as platelet rich plasma (PRP), cell therapies such as autologous chondrocyte implantation (ACI) and mesenchymal stem cells, growth factors and cytokines, gene therapy. Aim: This study aims to provide a clear definition of these technologies and describe the evidence supporting their clinical efficacy to treat osteoarthritis. This is to provide clarity to both clinicians and patients on the range of technologies available. Method: Literature databases Embase and PubMed were searched for keywords such as “biologic”, “osteoarthritis”. Results: The literature identified 4 primary categories of biologic treatments for osteoarthritis: stem cell therapy, somatic cell therapy, protein therapy and gene therapy. The evidence level varied in its quality from treatment to treatment, as did the conclusions of published studies. Conclusion: Autologous chondrocyte therapy had the most convincing evidence to support its use as a treatment for osteoarthritis, however, current methods of use produced variable results. Other treatments such as platelet rich plasma and bone marrow derived stem cells show promise as potential future therapies, with more refinement, but evidence does not support their use currently. Other treatments including autologous stem cells should be avoided until there is a greater quantity and quality of evidence supporting their use.展开更多
The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing ...The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor （VDR）, we examined their response to different concentrations of 25-hydroxy vitamin D3 [25（OH）D3] （100 or 500 nmol·L^-1） and 1,25-dihydroxy vitamin D3 [1,25（OH）2D3] （0.1 or 0.5 nmol·L^-1） metabolites in cell cultures. Specifically, CD14＋ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand （RANKL） and macrophage colony-stimulating factor （M-CSF）. Tartrate-resistant acid phosphatase （TRAP） histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue （ex vivo） by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR （qRT-PCR） was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L^-1 of 25（OH）D3 and 0.1-0.5 nmol·L^-1 of 1,25（OH）2D3, upregulating cytochrome P450 family 27 subfamily B member I （CYP27B1） and cytochrome P450 family 24 subfamily A member I （CYP24A1）. Osteoclast fusion transcripts transmembrane 7 subfamily member 4 （tm7sf4） and nuclear factor of activated T-cell cytoplasmic 1 （nfatcl） where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25（OH）D3 and 1,25（OH）2D3 reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25（OH）2D3 on osteoclasts in vitro may therefore provide insight into the effects of clinical vitamin D treatments, further providing a counterpoint to the high-dose effects reported from in vitro experiments.展开更多
Glucocorticoids remain the cornerstone of medicaltherapy in giant cell arteritis(GCA) and should be started immediately to prevent severe consequences of the disease, such as blindness. However, glucocorticoid therapy...Glucocorticoids remain the cornerstone of medicaltherapy in giant cell arteritis(GCA) and should be started immediately to prevent severe consequences of the disease, such as blindness. However, glucocorticoid therapy leads to significant toxicity in over 80% of the patients. Various steroid-sparing agents have been tried, but robust scientific evidence of their efficacy and safety is still lacking. Tocilizumab, a monoclonal IL-6 receptor blocker, has shown promising results in a number of case series and is now being tested in a multi-centre randomized controlled trial. Other targeted treatments, such as the use of abatacept, are also now under investigation in GCA. The need for surgical treatment is rare and should ideally be performed in a quiescent phase of the disease. Not all patients follow the same course, but there are no valid biomarkers to assess therapy response. Monitoring of disease progress still relies on assessing clinical features and measuring inflammatory markers(C-reactive protein and erythrocyte sedimentation rate). Imaging techniques(e.g., ultrasound) are clearly important screening tools for aortic aneurysms and assessing patients with largevessel involvement, but may also have an important role as biomarkers of disease activity over time or in response to therapy. Although GCA is the most common form of primary vasculitis, the optimal strategies for treatment and monitoring remain uncertain.展开更多
AIM To characterise the role of substitutes for receptoractivator nuclear factor kappa-B ligand(RANKL) in rheumatoid arthritis(RA) joint destruction. METHODS Synovial fluid(SF) macrophages isolated from the knee joint...AIM To characterise the role of substitutes for receptoractivator nuclear factor kappa-B ligand(RANKL) in rheumatoid arthritis(RA) joint destruction. METHODS Synovial fluid(SF) macrophages isolated from the knee joint of RA patients were incubated with 25 ng/m L macrophage-colony stimulating factor(M-CSF) and 50 ng/mL LIGHT(lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) in the presence and absence of 25 ng/mL RANKL and 100 ng/mL osteoprotegerin(OPG) on glass coverslips and dentine slices. Osteoclastogenesis was assessed by the formation of multinucleated cells(MNCs) expressing tartrate-resistant acid phosphatase(TRAP) on coverslips and the extent of lacunar resorption pit formation on dentine slices. The concentration of LIGHT in RA and osteoarthritis(OA) synovial fluid was measured by an enzyme-linked immunosorbent assay(ELISA) and the expression of LIGHT in RA and OA synovium was determined by immunohistochemistry using an indirect immunoperoxidase technique. RESULTS In cultures of RA SF macrophages treated with LIGHT and M-CSF, there was significant formation of TRAP + MNCs on coverslips and extensive lacunar resorption pit formation on dentine slices. SF-macrophage-osteoclast differentiation was not inhibited by the addition of OPG, a decoy receptor for RANKL. Resorption pits were smaller and less confluent than in RANKL-treated cultures but the overall percentage area of the dentine slice resorbed was comparable in LIGHT-and RANKL-treated cultures. LIGHT significantly stimulated RANKL-induced lacunar resorption compared with RA SF macrophages treated with either RANKL or LIGHT alone. LIGHT was strongly expressed by synovial lining cells, subintimal macrophages and endothelial cells in RA synovium and the concentration of LIGHT was much higher in RA compared with OA SF.CONCLUSION LIGHT is highly expressed in RA synovium and SF, stimulates RANKL-independent/dependent osteoclastogenesis from SF macrophages and may contribute to marginal erosion formation.展开更多
In the field of medical research,studies of organoids and organoid extracellular vesicles(OEVs)are leading a revolutionary change.1 Organoids are simplified,miniaturised versions of organs that simulate the microenvir...In the field of medical research,studies of organoids and organoid extracellular vesicles(OEVs)are leading a revolutionary change.1 Organoids are simplified,miniaturised versions of organs that simulate the microenvironment of human tissues,and have broad applications in disease modelling,drug development,and regenerative medicine.Extracellular vesicles(EVs)are tiny vesicles secreted from various cells,containing proteins,lipids,RNA,and other biomolecules.展开更多
In the dynamic landscape of generative artificial intelligence(GenAI),recent developments,such as the artificial research organisation OpenAI’s introduction of the text-to-video generation tool Sora,have again catapu...In the dynamic landscape of generative artificial intelligence(GenAI),recent developments,such as the artificial research organisation OpenAI’s introduction of the text-to-video generation tool Sora,have again catapulted GenAI into the limelight.Thus reigniting discussions on the swift march towards an era of future controlled usage of artificial general intelligence(AGI).Concurrently,in the realm of scientific research,the use of GenAI tools like DALL·E to generate inaccurate scientific illustrations for publication and the skepticism surrounding findings published in Nature from the AI-driven automated laboratory,A-Lab,have sparked widespread scientific controversy1.展开更多
Despite being over thirty years since there was proof that the hypothetical osteogenic stem cell existed,1 demonstration of any dramatic value for the use of such cells in orthopaedic clinical practice by tissue engin...Despite being over thirty years since there was proof that the hypothetical osteogenic stem cell existed,1 demonstration of any dramatic value for the use of such cells in orthopaedic clinical practice by tissue engineering approaches has not yet been realised.This is notwithstanding extensive studies concerning the likely nature and potentials of these cells in countless in vitro and in vivo investigations.In part,this is based on the confusion caused by exaggeration of claims by unreliable,or at best naïve,investigators and opportunistic entrepreneurs who have grossly misinterpreted data from many ill-conceived studies.2,3 This pseudo-science has been harmful,especially to the stem cell field,both academically and commercially.展开更多
For successful translational use of stem cells in biomedicine,knowledge of the quality of the cells,the presence of bioactive factors,and the nature of the microenvironmental niches is paramount.They may be regarded a...For successful translational use of stem cells in biomedicine,knowledge of the quality of the cells,the presence of bioactive factors,and the nature of the microenvironmental niches is paramount.They may be regarded as the Three Musketeers as they unite“All for one,one for all”1 to control the trafficking,survival,proliferation,and differentiation of stem cells.In this second themed issue of Biomaterials Translational,entitled“Application of Stem Cells in Translational Medicine:Stem Cells Part II”.展开更多
Dedifferentiation of cell identity to a progenitor-like or stem cell-like state with increased cellular plasticity is frequently observed in cancer formation.During this process,a subpopulation of cells in tumours acq...Dedifferentiation of cell identity to a progenitor-like or stem cell-like state with increased cellular plasticity is frequently observed in cancer formation.During this process,a subpopulation of cells in tumours acquires a stem cell-like state partially resembling to naturally occurring pluripotent stem cells that are temporarily present during early embryogenesis.Such characteristics allow these cancer stem cells(CSCs)to give rise to the whole tumour with its entire cellular heterogeneity and thereby support metastases formation while being resistant to current cancer therapeutics.Cancer development and progression are demarcated by transcriptional dysregulation.In this article,we explore the epigenetic mechanisms shaping gene expression during tumorigenesis and cancer stem cell formation,with an emphasis on 3D chromatin architecture.Comparing the pluripotent stem cell state and epigenetic reprogramming to dedifferentiation in cellular transformation provides intriguing insight to chromatin dynamics.We suggest that the 3D chromatin architecture could be used as a target for re-sensitizing cancer stem cells to therapeutics.展开更多
文摘Background: The number of people presenting with osteoarthritis is increasing due, largely, to an ageing population and advances in medical treatments. This is driving the demand for new clinical solutions and treatments for the disease. Biologic therapies have been touted as an adjunct, or even alternative to established treatments for osteoarthritis. The term “biologics” refers to protein-based therapeutics that are derived from the proteins of living organisms. These treatments include, but are not limited to: autologous blood products such as platelet rich plasma (PRP), cell therapies such as autologous chondrocyte implantation (ACI) and mesenchymal stem cells, growth factors and cytokines, gene therapy. Aim: This study aims to provide a clear definition of these technologies and describe the evidence supporting their clinical efficacy to treat osteoarthritis. This is to provide clarity to both clinicians and patients on the range of technologies available. Method: Literature databases Embase and PubMed were searched for keywords such as “biologic”, “osteoarthritis”. Results: The literature identified 4 primary categories of biologic treatments for osteoarthritis: stem cell therapy, somatic cell therapy, protein therapy and gene therapy. The evidence level varied in its quality from treatment to treatment, as did the conclusions of published studies. Conclusion: Autologous chondrocyte therapy had the most convincing evidence to support its use as a treatment for osteoarthritis, however, current methods of use produced variable results. Other treatments such as platelet rich plasma and bone marrow derived stem cells show promise as potential future therapies, with more refinement, but evidence does not support their use currently. Other treatments including autologous stem cells should be avoided until there is a greater quantity and quality of evidence supporting their use.
基金financial support from Orthopaedic Research UK (P 470)Arthritis Research UK (grant 20299 and Oxford EOTC)
文摘The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor （VDR）, we examined their response to different concentrations of 25-hydroxy vitamin D3 [25（OH）D3] （100 or 500 nmol·L^-1） and 1,25-dihydroxy vitamin D3 [1,25（OH）2D3] （0.1 or 0.5 nmol·L^-1） metabolites in cell cultures. Specifically, CD14＋ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand （RANKL） and macrophage colony-stimulating factor （M-CSF）. Tartrate-resistant acid phosphatase （TRAP） histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue （ex vivo） by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR （qRT-PCR） was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L^-1 of 25（OH）D3 and 0.1-0.5 nmol·L^-1 of 1,25（OH）2D3, upregulating cytochrome P450 family 27 subfamily B member I （CYP27B1） and cytochrome P450 family 24 subfamily A member I （CYP24A1）. Osteoclast fusion transcripts transmembrane 7 subfamily member 4 （tm7sf4） and nuclear factor of activated T-cell cytoplasmic 1 （nfatcl） where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25（OH）D3 and 1,25（OH）2D3 reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25（OH）2D3 on osteoclasts in vitro may therefore provide insight into the effects of clinical vitamin D treatments, further providing a counterpoint to the high-dose effects reported from in vitro experiments.
文摘Glucocorticoids remain the cornerstone of medicaltherapy in giant cell arteritis(GCA) and should be started immediately to prevent severe consequences of the disease, such as blindness. However, glucocorticoid therapy leads to significant toxicity in over 80% of the patients. Various steroid-sparing agents have been tried, but robust scientific evidence of their efficacy and safety is still lacking. Tocilizumab, a monoclonal IL-6 receptor blocker, has shown promising results in a number of case series and is now being tested in a multi-centre randomized controlled trial. Other targeted treatments, such as the use of abatacept, are also now under investigation in GCA. The need for surgical treatment is rare and should ideally be performed in a quiescent phase of the disease. Not all patients follow the same course, but there are no valid biomarkers to assess therapy response. Monitoring of disease progress still relies on assessing clinical features and measuring inflammatory markers(C-reactive protein and erythrocyte sedimentation rate). Imaging techniques(e.g., ultrasound) are clearly important screening tools for aortic aneurysms and assessing patients with largevessel involvement, but may also have an important role as biomarkers of disease activity over time or in response to therapy. Although GCA is the most common form of primary vasculitis, the optimal strategies for treatment and monitoring remain uncertain.
基金Supported by the Rosetrees Trust,No.242Arthritis Research Campaign(United Kingdom),No.18358.
文摘AIM To characterise the role of substitutes for receptoractivator nuclear factor kappa-B ligand(RANKL) in rheumatoid arthritis(RA) joint destruction. METHODS Synovial fluid(SF) macrophages isolated from the knee joint of RA patients were incubated with 25 ng/m L macrophage-colony stimulating factor(M-CSF) and 50 ng/mL LIGHT(lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) in the presence and absence of 25 ng/mL RANKL and 100 ng/mL osteoprotegerin(OPG) on glass coverslips and dentine slices. Osteoclastogenesis was assessed by the formation of multinucleated cells(MNCs) expressing tartrate-resistant acid phosphatase(TRAP) on coverslips and the extent of lacunar resorption pit formation on dentine slices. The concentration of LIGHT in RA and osteoarthritis(OA) synovial fluid was measured by an enzyme-linked immunosorbent assay(ELISA) and the expression of LIGHT in RA and OA synovium was determined by immunohistochemistry using an indirect immunoperoxidase technique. RESULTS In cultures of RA SF macrophages treated with LIGHT and M-CSF, there was significant formation of TRAP + MNCs on coverslips and extensive lacunar resorption pit formation on dentine slices. SF-macrophage-osteoclast differentiation was not inhibited by the addition of OPG, a decoy receptor for RANKL. Resorption pits were smaller and less confluent than in RANKL-treated cultures but the overall percentage area of the dentine slice resorbed was comparable in LIGHT-and RANKL-treated cultures. LIGHT significantly stimulated RANKL-induced lacunar resorption compared with RA SF macrophages treated with either RANKL or LIGHT alone. LIGHT was strongly expressed by synovial lining cells, subintimal macrophages and endothelial cells in RA synovium and the concentration of LIGHT was much higher in RA compared with OA SF.CONCLUSION LIGHT is highly expressed in RA synovium and SF, stimulates RANKL-independent/dependent osteoclastogenesis from SF macrophages and may contribute to marginal erosion formation.
基金supported by the National Natural Science Foundation of China(Nos.82230071,82202344)Integrated Project of Major Research Plan of National Natural Science Foundation of China(No.92249303).
文摘In the field of medical research,studies of organoids and organoid extracellular vesicles(OEVs)are leading a revolutionary change.1 Organoids are simplified,miniaturised versions of organs that simulate the microenvironment of human tissues,and have broad applications in disease modelling,drug development,and regenerative medicine.Extracellular vesicles(EVs)are tiny vesicles secreted from various cells,containing proteins,lipids,RNA,and other biomolecules.
基金financially supported by Integrated Project of Major Research Plan of National Natural Science Foundation of China(No.92249303)Young Elite Scientist Sponsorship Program by China Association for Science and Technology(No.YESS20230049).
文摘In the dynamic landscape of generative artificial intelligence(GenAI),recent developments,such as the artificial research organisation OpenAI’s introduction of the text-to-video generation tool Sora,have again catapulted GenAI into the limelight.Thus reigniting discussions on the swift march towards an era of future controlled usage of artificial general intelligence(AGI).Concurrently,in the realm of scientific research,the use of GenAI tools like DALL·E to generate inaccurate scientific illustrations for publication and the skepticism surrounding findings published in Nature from the AI-driven automated laboratory,A-Lab,have sparked widespread scientific controversy1.
文摘Despite being over thirty years since there was proof that the hypothetical osteogenic stem cell existed,1 demonstration of any dramatic value for the use of such cells in orthopaedic clinical practice by tissue engineering approaches has not yet been realised.This is notwithstanding extensive studies concerning the likely nature and potentials of these cells in countless in vitro and in vivo investigations.In part,this is based on the confusion caused by exaggeration of claims by unreliable,or at best naïve,investigators and opportunistic entrepreneurs who have grossly misinterpreted data from many ill-conceived studies.2,3 This pseudo-science has been harmful,especially to the stem cell field,both academically and commercially.
文摘For successful translational use of stem cells in biomedicine,knowledge of the quality of the cells,the presence of bioactive factors,and the nature of the microenvironmental niches is paramount.They may be regarded as the Three Musketeers as they unite“All for one,one for all”1 to control the trafficking,survival,proliferation,and differentiation of stem cells.In this second themed issue of Biomaterials Translational,entitled“Application of Stem Cells in Translational Medicine:Stem Cells Part II”.
基金Work in S.P.'s laboratory is supported by a Cancer Research UK Career Development Fellowship,Grant ID C59392/A25064Royal Society,UKand The Clarendon Fund and St Edmund Hall Scholarship,UK,SFF1920_CB_MSD_759707.
文摘Dedifferentiation of cell identity to a progenitor-like or stem cell-like state with increased cellular plasticity is frequently observed in cancer formation.During this process,a subpopulation of cells in tumours acquires a stem cell-like state partially resembling to naturally occurring pluripotent stem cells that are temporarily present during early embryogenesis.Such characteristics allow these cancer stem cells(CSCs)to give rise to the whole tumour with its entire cellular heterogeneity and thereby support metastases formation while being resistant to current cancer therapeutics.Cancer development and progression are demarcated by transcriptional dysregulation.In this article,we explore the epigenetic mechanisms shaping gene expression during tumorigenesis and cancer stem cell formation,with an emphasis on 3D chromatin architecture.Comparing the pluripotent stem cell state and epigenetic reprogramming to dedifferentiation in cellular transformation provides intriguing insight to chromatin dynamics.We suggest that the 3D chromatin architecture could be used as a target for re-sensitizing cancer stem cells to therapeutics.
