Neutralization of excessive levels of active TGF-β1 reduces MSC recruitment and differentiation to mitigate peritendinous adhesion

PPeritendinous adhesion formation(PAF)can substantially limit the range of motion of digits.However,the origin of myofibroblasts in PAF tissues is still unclear.In this study,we found that the concentration of active TGF-β1 and the numbers of macrophages,mesenchymal stromal cells(MSCs),and myofibroblasts in human and mouse adhesion tissues were increased.Furthermore,knockout of TGF-β1 in macrophages or TGF-β1R2 in MSCs inhibited PAF by reducing MSC and myofibroblast infiltration and collagenⅠandⅢdeposition,respectively.Moreover,we found that MSCs differentiated into myofibroblasts to form adhesion tissues.Systemic injection of the TGF-β–neutralizing antibody 1D11 during the granulation formation stage of PAF significantly reduced the infiltration of MSCs and myofibroblasts and,subsequently,PAF.These results suggest that macrophage-derived TGF-β1 recruits MSCs to form myofibroblasts in peritendinous adhesions.An improved understanding of PAF mechanisms could help identify a potential therapeutic strategy.

Adiponectin signalling in bone homeostasis,with age and in disease

Adiponectin is the most abundant circulating adipokine and is primarily involved in glucose metabolism and insulin resistance.Within the bone,osteoblasts and osteoclasts express the adiponectin receptors,however,there are conflicting reports on the effects of adiponectin on bone formation and turnover.Many studies have shown a pro-osteogenic role for adiponectin in in vivo murine models and in vitro:with increased osteoblast differentiation and activity,alongside lower levels of osteoclastogenesis.However,human studies often demonstrate an inverse relationship between adiponectin concentration and bone activity.Moreover,the presence of multiple isoforms of adiponectin and multiple receptor subtypes has the potential to lead to more complex signalling and functional consequences.As such,we still do not fully understand the importance of the adiponectin signalling pathway in regulating bone homeostasis and repair in health,with age and in disease.In this review,we explore our current understanding of adiponectin bioactivity in the bone;the significance of its different isoforms;and how adiponectin biology is altered in disease.Ultimately,furthering our understanding of adiponectin regulation of bone biology is key to developing pharmacological and non-pharmacological(lifestyle)interventions that target adiponectin signalling to boost bone growth and repair in healthy ageing,following injury or in disease.

Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts

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.

Long-term clinical performance of flapless implant surgery compared to the conventional approach with flap elevation:A systematic review and meta-analysis

BACKGROUND The conventional implant approach involves flap elevation,which may result in increased soft tissue and bone loss and postoperative morbidity.The flapless surgical technique,aided by three-dimensional medical imaging equipment,is regarded as a possible alternative to the conventional approach to alleviate the above issues.Several studies have been performed regarding the role of flapless implant surgery.However,the results are inconsistent and there is no robust synthesis of long-term evidence to better inform surgeons regarding which type of surgical technique is more beneficial to the long-term prognosis of patients in need of implant insertion.AIM To compare the long-term clinical performance after flapless implant surgery to that after the conventional approach with flap elevation.METHODS PubMed,EMBASE,Cochrane Central Register of Controlled Trials,and grey literature databases were searched from inception to 23 September 2019.Randomised controlled trials(RCTs)and cohort studies comparing the long-term clinical performance after flapless implant surgery to that after the conventional approach over a follow-up of three years or more were included.Meta-analyses were conducted to estimate the odds ratios(ORs)or mean differences(MDs)and their 95%confidence intervals(CIs)between the long-term implant survival rate,marginal bone loss,and complication rate of the flapless and conventional groups.Subgroup analyses were carried out to account for the possible effects of the guided or free-hand method during flapless surgery.RESULTS Ten articles,including four RCTs and six cohort studies,satisfied the eligibility criteria and nine of them were included in the meta-analysis.There was no significant difference between the long-term implant survival rate[OR=1.30,95%CI(0.37,4.54),P=0.68],marginal bone loss[MD=0.01,95%CI(-0.42,0.44),P=0.97],and complication rate[OR=1.44,95%CI(0.77,2.68),P=0.25]after flapless implant surgery and the conventional approach.Moreover,subgroup analyses revealed that there was no statistically significant difference between the implant survival rate[guided:OR=1.52,95%CI(0.19,12.35),P=0.70];free-hand:n=1,could not be estimated,marginal bone loss[guided:MD=0.22,95%CI(-0.14,0.59),P=0.23;free-hand:MD=-0.27,95%CI(-1.10,0.57),P=0.53],or complication rate[guided:OR=1.16,95%CI(0.52,2.63),P=0.71;free-hand:OR=1.75,95%CI(0.66,4.63),P=0.26]in the flapless and conventional groups either with use of the surgical guide or by the free-hand method.CONCLUSION The flapless surgery and conventional approach had comparable clinical performance over three years or more.The guided or free-hand technique does not significantly affect the long-term outcomes of flapless surgery.

Giant cell arteritis: Current treatment and management

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.

Declaration of transparency for each research article

“It is the responsibility of everyone involved to ensure that the published record is an unbiased,accurate representation of research”[1].The research record is often manipulated for short term gain but at the risk of harm to patients.The medical research community needs to implement changes to ensure that readers obtain the truth about all research,especially reports of randomised trials,which hold a special place in answering what works best for patients.

牛津单髁膝关节置换:长期结果(英文)

牛津膝置换是使用最广泛的膝关节单髁置换(UKR)。牛津膝在37年前开始应用,拥有一个全匹配的活动衬垫,因而磨损率非常低。牛津膝最主要的使用指征是膝关节前内侧骨关节炎,这种病人至少占所有需要行膝关节置换术患者的50%。由于这一系统的设计特点,传统UKR的反指征,如年龄、活动量、肥胖、髌股关节损害和软骨钙质沉着症等对于牛津膝均不是反指征。与全膝关节置换(TKR)相比,牛津膝提供更快的康复、更好的功能、更大的活动度和更好的术后满意度,发生并发症更少、程度更轻,病残率和死亡率更低。一个持续超过30年的研究显示在90%的病例中,牛津膝为患者终生提供了优或良的临床结果,且不需要翻修。在最近15年,牛津膝通过微创手术入路植入,涉及6000多例使用该入路牛津膝置换的9个研究报道显示,10年生存率约95%。在许多这样的研究中,医生们在拟行膝关节置换的患者中约50%使用了牛津单髁膝置换。

A brief history of the development of stromal stem cells (stem cells of the skeleton)

In all aspects of communication the meanings of words and definitions are of paramount importance for clear understanding and transmission of ideas.However,these meanings may change with time so that words and phrases take on different interpretations.Furthermore,the way words are used in writing significantly affects the conveyance of ideas from one mind to another.1 In the long history of the study of the histogenesis of bone we see some of these changes in meaning and understanding of concepts that have perhaps contributed to serious misinterpretation of the ideas of some investigators in the field.It is hoped that this brief historical perspective may explain and clarify at least some of the problems that have resulted.

Orthopaedic tissue engineering and stem cells -an unfulfilled promise

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.

平衡越好，跌倒越少鼓励老年女性参与平衡训练

跌倒是老年人群的一个重大问题，因为其常见并可能导致受伤以及生活质量降低。年龄相关的肌肉强度和神经系统减退会引起行走不稳。进一步引起行动时缺乏信心，某些人会发生严重跌倒。众所周知，强度和平衡训练在预防跌倒和改善行动能力及信心方面效果显著。大多数研究持续最多1年，研究项目需要老年人的时问和精力投入，并不总为大众所接受。

Stem cell fate and microenvironment

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”.

3D chromatin architecture and epigenetic regulation in cancer stem cells

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.

Advanced Robotics to Address the Translational Gap in Tendon Engineering

Tendon disease is a significant and growing burden to healthcare systems.One strategy to address this challenge is tssueengineering.A widely held view in this feld is that mechanical stimulation provided to constructs should replicate themechanicaienvironment of native tissue as closely as possible.We review recent tendon tissue engineering studies inthisarticle and highlight limitations of conventional uniaxial tensile bioreactors used in current literature.Advanced roboticplatforms such as musculoskeletal humanoid robots and soft robotic actuators are promising technologies which may helpaddress translational gaps in tendon tissue engineering We suggest the proposed benets of these technologies and identifyrecent studies which have worked to implement these technologies in tssue engineering.Lastly,key chalenges to addressinadapting these robotic technologies and proposed future research directions for tendon tssue engineering are discussed.

Application of stem cells in translational medicine

We are pleased to devote the following two issues of Biomaterials Translational to the important subject of the potential translation of stem cells for regenerative medicine and disease treatment.Stem cells with capacities to renew their own tissue are now considered present in all tissues and organs of the body.Such cells have been of great interest to biologists and clinicians over the past century,since Haeckel in his‘Natural history of creation’first coined the term in 1868.1 The nature of the definition of what constitutes a stem cell has changed with time,but since the 1970s there has been an explosion of research publications on stem cells(Figure 1).This has involved increasing consideration of these primitive cells,that exist in the embryo and postnatally,for translation to the clinic for medical use and significant public health benefit.The trend in research output continues to increase exponentially with almost 72,000 publications on stem cells being recorded in the past year alone(searched using Web of Science databases).Hence there is great urgency and adequate justification for dedication of appreciable journal emphasis to this topic.In this issue,Stem Cells-Part I,there are a variety of topics within this theme that are covered either as viewpoint,review or research papers.