Publications by authors named "Chunli Song"

96 Publications

Association Between Vitamin D Status and Undernutrition Indices in Children: A Systematic Review and Meta-Analysis of Observational Studies.

Front Pediatr 2021 4;9:665749. Epub 2021 Jun 4.

Department of Pediatrics, Dezhou People's Hospital, Dezhou, China.

Undernutrition, defined as stunting, wasting, and underweight, still implicates millions of infants and children worldwide. Micronutrients have pivotal effects on growth rate. The outcomes of vitamin D deficiency on undernutrition indices have stayed controversial. The object of current study is to answer this question: is there any association between vitamin D status and undernutrition indices? The international databases were used for a systematic search to identify relevant observational studies in English up to January 2021. A random-effect model was applied to combine the results of included essays. Among 3,400 citations, 7 observational studies (4 cohorts and 3 cross-sectional) were eligible to enter in meta-analysis. Analysis of the lowest 8,295 children indicated that low vs. high serum level of vitamin D is directly associated with a higher risk of wasting (Summary Risk Estimate: 1.30; 95% CI: 1.04, 1.62; = 0%). However, there is no significant association between vitamin status and risk of stunting (Summary Risk Estimate: 1.10; 95% CI: 0.72, 1.70; = 81.6%) and underweight (Summary Risk Estimate: 1.12; 95% CI: 0.81, 1.56; = 49.2%). When comparing low and high serum vitamin D concentration categories, there is an inverse link between vitamin D status and wasting, but no relationship with stunting as well as underweight. However, further prospective and trial studies are required to deepen our understanding of these associations.
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http://dx.doi.org/10.3389/fped.2021.665749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211725PMC
June 2021

Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species.

Cell 2021 06 24;184(13):3438-3451.e10. Epub 2021 May 24.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.
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http://dx.doi.org/10.1016/j.cell.2021.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142884PMC
June 2021

Perspectives of research ethics committee members on human challenge studies in the development of vaccines against COVID-19: a mixed methods study.

Ann Palliat Med 2021 Jun 7;10(6):6259-6269. Epub 2021 Jun 7.

Ethics Committee for Medical Scientific Research, Peking University Third Hospital, Beijing, China; Department of Orthopedics, Peking University Third Hospital, Beijing, China.

Background: Vaccines are considered the most effective protection against the coronavirus disease 2019 (COVID-19). Human Challenge Studies can help to shorten the development process of vaccines. The reviewers' opinions from research ethics committees (REC) play an essential gate-keeping role in determining whether a clinical trial can be conducted or not.

Methods: A convergent mixed-methods study was conducted in a leading general hospital in China. A total of 58 REC members from the institution were invited to participate in an online questionnaire survey. According to the result of the quantitative survey, 15 of these REC members were purposefully selected to participate in qualitative interviews further. Quantitative data were analyzed using descriptive statistical techniques, and thematic analysis was used to analyze the qualitative data. Findings from the quantitative and qualitative analyses were synthesized to deeply illustrate the attitudes, views, and suggestions of REC members on human challenge studies to develop COVID-19 vaccination.

Results: The response rate of the online questionnaire was 62% (36/58), and 15 of the respondents were interviewed. All participants deemed that the human challenge study should provide compensation to its participants and that sufficiently informed consent is necessary. The human challenge study was disagreed with by 38.9% of participants. The key points of concern raised were representativeness and fairness of participant selection, benefit, and risk, vulnerable groups, compensation to participants, informed consent, and general view on human challenge studies.

Conclusions: Human challenge studies helped accelerate the development of vaccines for disease control to a certain extent, but the bottom line of medical ethics should not have been broken. At any time, the rights and interests of research participants should come first.
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http://dx.doi.org/10.21037/apm-20-2622DOI Listing
June 2021

Long-term pretreatment with alendronate inhibits calvarial defect healing in an osteoporotic rat model.

J Bone Miner Metab 2021 Jun 6. Epub 2021 Jun 6.

Department of Orthopedics, Peking University Third Hospital, No. 49, Huayuan North Road, Haidian District, Beijing, 100191, China.

Introduction: This study aimed to observe the effects of long-term alendronate pretreatment on the healing of osteoporotic calvarial defects, and further investigate the effect of alendronate combined with once-weekly parathyroid hormone following 12 weeks of alendronate treatment in ovariectomized rats.

Materials And Methods: Thirty 3-month-old female rats were ovariectomized, and 24 rats received alendronate for 12 weeks. Then, a critical defect was created in the calvaria of all animals. Immediately after osteotomy, the animals received one of five treatments for 8 weeks: (1) continuation of vehicle (group E), (2) alendronate followed by vehicle (group A), (3) continuation of alendronate (group B), (4) alendronate followed by once-weekly parathyroid hormone alone (group C), or (5) continuation of alendronate combined with once-weekly parathyroid hormone (group D). Calvarial defect healing was assessed using dual-energy X-ray absorptiometry, micro-computed tomography, histology, and sequential fluorescence labeling.

Results: Group E showed a significantly higher volume of newly formed bone than groups A, B, C, and D. Evidence of new dense bone formation in group E was observed histologically. In addition, the immunohistochemical expression of runt-related transcription factor 2 was increased in group E but inhibited in groups A, B, C, and D. Sequential immunofluorescence also showed inhibited mineral apposition in groups A, B, C, and D compared with group E.

Conclusion: The present study shows that long-term pretreatment with alendronate inhibited calvarial defect healing in osteoporotic rats, and this effect could not be reversed by stopping alendronate, switching to parathyroid hormone, or combining with once-weekly parathyroid hormone.
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http://dx.doi.org/10.1007/s00774-021-01235-0DOI Listing
June 2021

Effect of weekly teriparatide injections on osteoporotic fracture healing: protocol for a double-blind, randomised controlled trial.

BMJ Open 2021 04 1;11(4):e043137. Epub 2021 Apr 1.

Department of Orthopedics, Peking University Third Hospital, Beijing, China

Introduction: Both animal studies and clinical trials have shown that daily parathyroid hormone administration promotes bone fracture healing. We previously found that weekly injections of the recombinant human parathyroid hormone teriparatide at a dosage of 20 μg/kg promoted tibial fracture healing to the same extent as daily injections of teriparatide at a dosage of 10 μg/kg in a rodent model. However, the effect of weekly teriparatide administration on human fracture healing is unreported. This protocol describes a randomised controlled clinical trial designed to evaluate whether weekly administration of teriparatide accelerates fracture repair in humans.

Methods And Analysis: This single-centre, double-blind, randomised controlled trial will be conducted in Peking University Third Hospital. Eligible patients with Colles' fracture incurred within 48 hours will be randomly divided into two groups (n=40 per group) that will receive 14 weekly subcutaneous injections of either saline or teriparatide (40 μg/week). The primary outcome will be the time taken to achieve radiographic healing, as assessed using the modified radiographic union scale for tibial fractures. The secondary outcomes will be functional assessments, including the self-administered Patient-Rated Wrist Evaluation questionnaire, grip strength and rate of fracture non-union.

Ethics And Dissemination: Ethical approval has been obtained from the Peking University Third Hospital Medical Science Research Ethics Committee (M2020207). The findings will be disseminated in peer-reviewed publications.

Trial Registration Number: NCT04473989: protocol version: 1.
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http://dx.doi.org/10.1136/bmjopen-2020-043137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021745PMC
April 2021

Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.

Front Pharmacol 2020 20;11:574720. Epub 2020 Nov 20.

Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0-72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (R) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, R was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.
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http://dx.doi.org/10.3389/fphar.2020.574720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919379PMC
November 2020

Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients.

Front Pharmacol 2020 12;11:585021. Epub 2021 Feb 12.

Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant and experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.
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http://dx.doi.org/10.3389/fphar.2020.585021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907647PMC
February 2021

Combination Therapy of PTH and Antiresorptive Drugs on Osteoporosis: A Review of Treatment Alternatives.

Front Pharmacol 2020 27;11:607017. Epub 2021 Jan 27.

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

Antiresorptive drugs have been widely used for osteoporosis. Intermittent parathyroid hormone (PTH), an anabolic agent, increases osteoblast production rate and inhibits apoptosis of osteoblasts, thus increasing skeletal mass besides improving bone microarchitecture and strength. Combination therapy for osteoporosis produced great interests and controversies. Therefore, we performed a systematic literature search from PubMed, EMBASE, Scopus, Web of Science, CINDHL, and the Cochrane Database of Systematic Reviews using the search terms PTH or teriparatide combined with bisphosphonate, alendronate, ibandronate, risedronate, raloxifene, denosumab, and zoledronic acid with the limit osteoporosis. At last, 36 related articles were included for further analysis. Findings from previous studies revealed that combination therapy in different conditions of naive or previous bisphosphonate treatment might have different outcomes. The use of combination therapy, however, may be an alternative option among osteoporotic patients with a history of bisphosphonate use. Combined teriparatide with denosumab appear to show the most substantial and clinically relevant skeletal benefits to osteoporotic patients. Additional research is necessary to define optimal methods of developing sequential and/or cyclical combinations of PTH and antiresorptive agents.
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http://dx.doi.org/10.3389/fphar.2020.607017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874063PMC
January 2021

The effect of topical administration of simvastatin on entochondrostosis and intramembranous ossification: An animal experiment.

J Orthop Translat 2021 May 27;28:1-9. Epub 2021 Jan 27.

Department of Orthopedics, Peking University 3rd Hospital, Beijing Key Laboratory of Spinal Disease Research, Beijing, PR China.

Background: Simvastatin, a drug for lowering serum cholesterol, has been shown to enhance bone regeneration, but few studies have qualitatively and quantitatively tested its effect when used topically in different animal models. This study aims to investigate topical administration of simvastatin as a bone regeneration inducer by testing its effect on bone formation in both long tubular bone and flat bone defect, and the mechanism involved.

Methods: Two animal models were used for testing the effect of simvastatin on entochondrostosis and intramembranous ossification respectively. Simvastatin of different dosages combined with poly lactic acid were implanted in extreme radial defects of 12 adult male New Zealand rabbits. Bone formation was monitored using x-ray and CT-scan and measured using x-ray scales, pixel values and spiral CT-scan for 16 weeks before being subject to histological and immunohistochemistry examination. The result was compared with that of autograft and blank control groups. Simvastatin with thrombin and fibrin sealant were implanted in calvarial defects of three Rhesus monkeys and monitored for 18 weeks. Bone formation was compared between the simvastatin and the blank control group using spiral CT-scan and histological examination.

Results: Both visual and quantitative measurements by x-ray and spiral CT-scan indicated significant bone formation in radial defects in all simvastatin groups and the autograft group whereas no bone formation was found in control groups. There was no significant difference in bone formation quantity between 100 ​mg simvastatin and autograft. Histological and immunohistochemistry examination indicated entochondrostosis in association with positive expression of BMP-2 and HIF-1 alpha. Spiral CT-scan and histological examination of calvarial defects of monkeys showed intramembranous ossification after simvastatin implantation. No change was found in the control group.

Conclusions: Topical administration of simvastatin induces entochondrostosis and intramembranous ossification by enhancing expression of BMP-2 and HIF-1 alpha. The effect of simvastatin on bone regeneration is comparable to autograft.

The Translational Potential Of This Article: Topical administration of simvastatin can repair bone defect in both long tubular bones and flat bones of rabbits and monkeys as effectively as autograft. Given that it is cheap, safe and already in clinical use, simvastatin might be considered as a bone regeneration inducer with great potential.
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http://dx.doi.org/10.1016/j.jot.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844440PMC
May 2021

Time-Dependent Distribution of Hydroxychloroquine in Cynomolgus Macaques Using Population Pharmacokinetic Modeling Method.

Front Pharmacol 2020 14;11:602880. Epub 2021 Jan 14.

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

To evaluate the biodistribution of hydroxychloroquine (HCQ) in cynomolgus macaques and receive dynamic quantitative relationship between plasma, blood, and lung tissue concentration using the population pharmacokinetic modeling method, seventeen cynomolgus macaques were divided into six groups according to different HCQ dosing regimens over 5 days. The monkeys were euthanized, and blood, plasma, urine, feces and ten tissues were collected. All the samples were prepared by protein precipitation and analyzed by HPLC-MS/MS detection. The population pharmacokinetics of HCQ in the plasma, red blood cells, and lung tissue was conducted and simulated via ADAPT program. Results demonstrated that the maximum concentration ( ) of HCQ was 292.33 ng/mL in blood and 36.90 ng/mL in plasma after single dose of 3 mg/kg. The value of area under curve (AUC) was determined as 5,978.94 and 363.31 h* ng/mL for the blood and plasma, respectively. The descending order of the tissue-to-plasma concentration ratio was liver > spleen > kidney > lung > heart > subcutaneous fat > brain. The tissue-to-plasma concentration ratio and the tissue-to-blood concentration ratio for lung were found to be time-dependent with 267.38 and 5.55 at 120 h postdose, respectively. A five-compartment model with first-order oral absorption and elimination best described the plasma, blood, and lung tissue pharmacokinetics. The estimated elimination rate constant (ke) for a typical monkey was 0.236 h. The volume of distribution in central (Vc/F) and other two peripheral compartments (Vb/F and Vl/F) were 114, 2.68, and 5.55 L, respectively. Model-based simulation with PK parameters from cynomolgus macaques showed that the ratio of the blood or plasma to lung tissue was a dynamic change course, which suggested that the rate of HCQ concentration decrease in the blood or plasma was faster than that in the lung tissue. HCQ was found to be accumulated in tissues, especially in the liver, kidney, lung, and spleen. Also, the tissue-to-plasma concentration ratio increased over time. The population pharmacokinetic model developed could allow for the assessment of pharmacokinetics-pharmacodynamics relationships, especially relevant tissue concentration-response for HCQ. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
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http://dx.doi.org/10.3389/fphar.2020.602880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841297PMC
January 2021

Cellular alterations and crosstalk in the osteochondral joint in osteoarthritis and promising therapeutic strategies.

Connect Tissue Res 2021 Jan 17:1-11. Epub 2021 Jan 17.

Department of Orthopaedics, Peking University Third Hospital, Beijing, China.

Osteoarthritis (OA) is a joint disorder involving cartilage degeneration and subchondral bone sclerosis. The bone-cartilage interface is implicated in OA pathogenesis due to its susceptibility to mechanical and biological factors. The crosstalk between cartilage and the underlying subchondral bone is elevated in OA due to multiple factors, such as increased vascularization, porosity, microcracks and fissures. Changes in the osteochondral joint are traceable to alterations in chondrocytes and bone cells (osteoblasts, osteocytes and osteoclasts). The phenotypes of these cells can change with the progression of OA. Aberrant intercellular communications among bone cell-bone cell and bone cell-chondrocyte are of great importance and might be the factors promoting OA development. An appreciation of cellular phenotypic changes in OA and the mechanisms by which these cells communicate would be expected to lead to the development of targeted drugs with fewer side effects.
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http://dx.doi.org/10.1080/03008207.2020.1870969DOI Listing
January 2021

Once-weekly parathyroid hormone combined with ongoing long-term alendronate treatment promotes osteoporotic fracture healing in ovariectomized rats.

J Orthop Res 2020 Dec 16. Epub 2020 Dec 16.

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

This study examined the effect of once-weekly parathyroid hormone (PTH) combined with alendronate upon osteoporotic fracture healing after long-term alendronate anti-osteoporosis therapy. Seventy-six 12-week-old female Sprague-Dawley rats were either sham operated or bilaterally ovariectomized (OVX). Following confirmation of osteoporosis 3 months after OVX, the remaining 64 animals received alendronate therapy. After 3 months of alendronate treatment, all rats underwent unilateral transverse tibial osteotomy. Animals were immediately randomly assigned to one of four groups: (1) alendronate followed by vehicle (ALN-VEH), (2) continuation of alendronate (ALN-ALN), (3) alendronate followed by once-weekly PTH alone (ALN-PTH), (4) continuation of alendronate combined with once-weekly PTH (ALN-ALN + PTH) until collection at 4 or 8 weeks after osteotomy. The fractured tibia was assessed using x-ray, dual-energy x-ray absorptiometry, microcomputed tomography, biomechanical testing, histology, and sequential fluorescence labeling. The ALN-ALN + PTH treatment significantly increased total callus volume, mineralized callus volume, mineralized callus volume/total callus volume, and biomechanical strength of the callus relative to ALN-VEH and ALN-PTH treatments at both 4 and 8 weeks and produced more mature trabecular bone compared with ALN-ALN treatment at 8 weeks. RANKL/osteoprotegerin (OPG) are osteoclastogenesis markers, while cluster of differentiation 31 (CD31) is an important marker of angiogenesis. Qualitative immunohistochemical analysis revealed that CD31 and OPG expression was was strong after ALN-ALN + PTH compared with ALN-ALN treatment, whereas RANKL expression was weak after ALN-ALN + PTH versus ALN-PTH treatment. Our study showed that once-weekly PTH combined with alendronate was beneficial in promoting the healing of fractures acquired after long-term alendronate therapy in OVX-induced osteoporotic rats.
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http://dx.doi.org/10.1002/jor.24953DOI Listing
December 2020

Stem cell-derived exosomes: Role in the pathogenesis and treatment of atherosclerosis.

Int J Biochem Cell Biol 2021 01 20;130:105884. Epub 2020 Nov 20.

Department of Cardiology, Second Hospital of Jilin University, Chang Chun, 130012, China. Electronic address:

Atherosclerosis (AS) is a chronic inflammatory vascular disease characterized by the accumulation of lipids and inflammatory debris in large arteries, high morbidity, and AS-related disease mortality. AS is a complex process, involving endothelial cell dysfunction and inflammation, smooth muscle cell proliferation, and macrophage activation. However, the currently available therapies for AS are not ideal, thus requiring development of novel treatment strategies. Exosomes are bi-lipid membranous extracellular containing multifarious cargo, such as proteins, lipids, micro ribonucleic acid (miRNAs), messenger RNAs, and long non-coding RNAs. Moreover, exosomes reportedly participate in various AS processes. Specifically, stem cell-derived exosomes can regulate the occurrence and development of AS, exhibiting the ability to overcome the limitations associated with AS treatment and stem cell therapy. In this paper, we review the pathological mechanism of AS and discuss the role of exosomes and stem cell-derived exosomes in AS progression. We conclude by suggesting new therapeutic strategies for treating AS with stem cell-derived exosomes in the hope of improving the clinical treatment of AS.
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http://dx.doi.org/10.1016/j.biocel.2020.105884DOI Listing
January 2021

Gut microbiome dysbiosis alleviates the progression of osteoarthritis in mice.

Clin Sci (Lond) 2020 12;134(23):3159-3174

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

Gut microbiota dysbiosis has been studied under the pathological conditions of osteoarthritis (OA). However, the effect of antibiotic-induced gut flora dysbiosis on OA remains incompletely understood at present. Herein, we used a mouse (8 weeks) OA model of destabilization of the medial meniscus (DMM) and gut microbiome dysbiosis induced by antibiotic treatment with ampicillin and neomycin for 8 weeks. The results show that antibiotic-induced intestinal microbiota dysbiosis reduced the serum level of lipopolysaccharide (LPS) and the inflammatory response, such as suppression of the levels of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which can lead to decreased matrix metalloprotease-13 (MMP-13) expression and improvement of OA after joint injury. In addition, trabecular thickness (Tb.Th) and osteophyte scores were increased significantly in antibiotic-induced male mice compared with female mice. We further used network correlation analysis to verify the effect of gut microbiota dysbiosis on OA. Therefore, the present study contributes to our understanding of the gut-joint axis in OA and reveals the relationship between the inflammatory response, sex and gut microbiota, which may provide new strategies to prevent the symptoms and long-term sequelae of OA. Conclusion: Our data showed that gut microbiome dysbiosis alleviates the progression of OA.
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http://dx.doi.org/10.1042/CS20201224DOI Listing
December 2020

Effect of Single Versus Multiple Fractures on Systemic Bone Loss in Mice.

J Bone Miner Res 2021 Mar 10;36(3):567-578. Epub 2020 Dec 10.

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

Systemic bone loss after initial fracture contributes to an increased risk of secondary fracture. Clinical research has revealed an association between the risk of future fracture and the number or magnitude of prior fractures. However, the change in systemic bone mass after single versus multiple fractures is unknown. We used ipsilateral femur and tibia fractures as multiple fractures and a femur or tibia fracture as a single fracture to investigate the influence of single versus multiple fractures on systemic bone mass. Seventy-two adult male C57BL/6J mice underwent transverse osteotomies of the ipsilateral femur and/or tibia with subsequent internal fixation. The dynamic change of in vivo whole-body BMD was assessed at 4 days, 2 weeks, and 4 weeks after fracture. The microstructure of the L vertebral body and contralateral femur was assessed using micro-CT (μCT) and biomechanical tests (vertebral compression test and three-point bending test) at 2 and 4 weeks. Tartrate-resistant acid phosphatase (TRAP) staining, sequential fluorescence labeling, and systemic inflammatory cytokines were also quantified. A greater decrease in whole-body BMD was observed after multiple than single fractures. The trabecular bone volume fraction, trabecular number, and trabecular thickness of the L vertebral body were significantly reduced. There were no significant differences in cortical thickness, trabecular bone microstructure, or bone strength in the contralateral femur. At 4 days and 2 weeks, we observed significant increases in the serum levels of IL-6 and TNF-α. We also observed an increase in the osteoclast number of the L vertebral body at 4 days. These data indicate that systemic bone loss might increase with the number or severity of prior fractures, and the mechanism may be partly associated with an increased osteoclast number and a more severe inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4211DOI Listing
March 2021

Neutrophil Surface CD64 Stimulation Index Detection Assay in Diagnosing Mycobacterium tuberculosis Infection.

Clin Lab 2020 Nov;66(11)

Background: This study aimed to develop a method for assessing the sensitivity and diagnostic performance of the neutrophil surface CD64 stimulation index (SI) in tuberculosis infection.

Methods: A total of 149 samples were divided into three groups (tuberculosis group, n = 51; nontuberculosis infection group, n = 50; and healthy control group, n = 48). Flow cytometry was used to detect the sensitivity of CD64 SI on the surface of neutrophils. The sensitivities of CD64 SI before and after stimulation with ESAT-6 and CFP-10 antigens were compared using interferon-gamma release assay-enzyme-linked immunosorbent assay (IGRA-ELISA).

Results: The diagnostic threshold for CD64 SI based on the receiver operating characteristic curve was found to be 2.025, which is the standard for judging tuberculosis infection. The IGRA-ELISA and the CD64 SI assays were highly consistent with a kappa value of 0.635 (p < 0.003, 95% CI: 0.002 - 0.003).

Conclusions: The neutrophil surface CD64 SI value detection method may serve as one of the new diagnostic methods for active Mycobacterium tuberculosis infection.
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http://dx.doi.org/10.7754/Clin.Lab.2020.200214DOI Listing
November 2020

Roles of exosomal miRNA in vascular aging.

Pharmacol Res 2021 03 6;165:105278. Epub 2020 Nov 6.

Department of Cardiology, The Second Hospital of Jilin University, Changchun 130041, China. Electronic address:

Aging is a major risk factor for human diseases. As global average life expectancy has lengthened, delaying or reducing aging and age-related diseases has become an urgent issue for improving the quality of life. The vascular aging process represents an important link between aging and age-related diseases. Exosomes are small extracellular vesicles (EV) that can be secreted by almost all eukaryotic cells, and they deliver characteristic biological information about donor cells to regulate the cellular microenvironment, mediate signal transmission between neighboring or distant cells, and affect the expression of target genes in recipient cells. Many recent studies have shown that exosomal microribonucleic acids (miRNA) are involved in the regulation of vascular aging by participating in the physiological functions of vascular cells and the destruction and remodeling of the extracellular matrix (ECM). This review summarizes the regulatory functions of exosomal miRNA in vascular aging because they interact with the ECM, and participate in vascular cell senescence, and the regulation of senescence-related functions such as proliferation, migration, apoptosis, inflammation, and differentiation.
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http://dx.doi.org/10.1016/j.phrs.2020.105278DOI Listing
March 2021

Osteogenic effects in a rat osteoporosis model and femur defect model by simvastatin microcrystals.

Ann N Y Acad Sci 2021 03 23;1487(1):31-42. Epub 2020 Oct 23.

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

Simvastatin is a translational drug that may be used to induce local bone formation. In this study, simvastatin microcrystals were made by a wet media milling method, and then we verified the osteogenic effect of the microcrystals in rat ovariectomy (OVX)-induced osteoporosis and femur defect models. For the osteoporosis model, we delivered simvastatin microcrystals to the tibia with poloxamer hydrogels via an intraosseous injection. Bone mineral density and the ultimate force of the treated tibia were significantly improved after injection of simvastatin microcrystals at 0.5 and 1 mg compared with the OVX or 0-mg control groups. For the femur defect model, simvastatin microcrystals were incorporated in clinically used calcium phosphate cements (CPCs) as an implant. Quantitative analysis of bone regeneration by microcomputed tomography (μCT) showed improved bone morphology with simvastatin microcrystals at 50 and 100 μg, compared with the CPC vehicle. A semiquantitative scale for histology assessment further demonstrated a higher bone regeneration score in the drug-loaded groups. Our study shows that simvastatin microcrystals can promote bone formation by local delivery using a poloxamer hydrogel or CPC, which may be translationally useful.
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http://dx.doi.org/10.1111/nyas.14513DOI Listing
March 2021

Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model.

Eur J Med Chem 2021 Jan 18;209:112842. Epub 2020 Sep 18.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address:

Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC (half maximal effective concentration) value of 0.0005 μM in the erastin-induced HT1080 cell ferroptosis model. In the MCAO (middle cerebral artery occlusion) ischemic stroke model, 51 presented an excellent therapeutic effect. This compound also displayed favorable pharmacokinetic properties, in particular, a good ability to permeate the blood-brain barrier. Overall, 51 could be a promising lead compound for the treatment of ferroptosis related diseases and deserves further investigations.
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http://dx.doi.org/10.1016/j.ejmech.2020.112842DOI Listing
January 2021

Single-dose local intraosseous injection of simvastatin suppresses breast cancer with tumor vascular normalization.

Transl Oncol 2020 Dec 18;13(12):100867. Epub 2020 Sep 18.

Department of Orthopedics, Peking University Third Hospital, Beijing Key Laboratory of Spinal Disease, Beijing, China. Electronic address:

Tumor vessels play important roles in cancer development and angiogenesis has been characterized as an essential process for tumor cell tumor growth. Our previous studies found that a single-dose local intraosseous simvastatin injection rapidly and long-termly mobilized bone marrow-derived endothelial progenitor cells to peripheral blood, promoting angiogenesis and ameliorating ischemia injury. However, whether intraosseous injection of simvastatin participates in cancer progression and the role of angiogenesis enhancement in this process remain unknown. In this study, we found that intraosseous injection of simvastatin improves tumor vascular structure, along with increasing the percentage of pericyte coverage on tumor vessels, and reducing vascular permeability, tumor hypoxia and tumor necrosis. Further, we demonstrate that a single-dose local intraosseous simvastatin injection suppresses tumor growth, facilitates sensitivity of chemotherapy and prolongs survival in breast cancer-bearing mice. In addition, oral application, intravenous, subcutaneous and intraperitoneal injection of simvastatin do not show these effects. Taken together, these results demonstrate that intraosseous injection of simvastatin suppresses breast cancer with tumor vascular normalization, which might be a promising strategy for cancer treatment.
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http://dx.doi.org/10.1016/j.tranon.2020.100867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509234PMC
December 2020

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model.

Acta Pharm Sin B 2020 Jul 20;10(7):1216-1227. Epub 2020 Apr 20.

Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China.

Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2-5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2-3: 500 mg BID, Days 4-5: 250 mg BID, CQ phosphate), and other vulnerable populations (.., renal and hepatic impairment and elderly patients, Days 1-5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.
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http://dx.doi.org/10.1016/j.apsb.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252145PMC
July 2020

Biogenesis, Features, Functions, and Disease Relationships of a Specific Circular RNA: CDR1as.

Aging Dis 2020 Jul 23;11(4):1009-1020. Epub 2020 Jul 23.

Department of Cardiovascular Internal Medicine, the Second Hospital of Jilin University, Changchun, China.

In 2011, Hansen discovered the natural antisense transcript (NAT) of the cerebellar degeneration-related protein 1 gene (CDR1), and further described CDR1 NAT as a circular RNA (CircRNA). CDR1 antisense RNA (CDR1as), which is the official name of CDR1 NAT, is conserved and extensively expressed in most eutherian mammal brains and other specialized tissues. Further studies have elucidated its biogenesis, features, functions, and relationships with diseases. CDR1as is involved in many disease processes as a microRNA (miR) sponge. Therefore, it seems that further research on CDR1as could facilitate the diagnosis and treatment of some diseases, such as cancer and diabetes. However, a detailed analysis of the results of studies on CDR1as revealed that they are inconsistent and make unclear conclusions. In this review, we gathered and analyzed the recent studies about CDR1as in detail and aimed to elucidate accurate conclusions from them.
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http://dx.doi.org/10.14336/AD.2019.0920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390531PMC
July 2020

Incidence of and trends in hip fracture among adults in urban China: A nationwide retrospective cohort study.

PLoS Med 2020 08 6;17(8):e1003180. Epub 2020 Aug 6.

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

Background: Hip fracture is a public health concern because of its considerable morbidity, excess mortality, great risk of disability, and high societal healthcare costs. China has the largest population of older people in the world and is experiencing rapid population aging and facing great challenges from an increasing number of hip fractures. However, few studies reported the epidemiology, especially at a national level. We aimed to evaluate trends in hip fracture incidence and associated costs for hospitalization in China.

Methods And Findings: We conducted a population-based study using data between 2012 and 2016 from the national databases of Urban Employee Basic Medical Insurance and Urban Resident Basic Medical Insurance in China, covering about 480 million residents. Data from around 102.56 million participants aged 55 years and older during the study period were analyzed. A total of 190,560 incident hip fracture patients (mean age 77.05 years, standard deviation 8.94; 63.99% female) were identified. Primary outcomes included the age- and sex-specific incidences of hip fracture. Associated annual costs for hospitalization were also calculated. Incidence was described as per 100,000 person-years at risk, and 95% confidence intervals were computed assuming a Poisson distribution. Hip fracture incidence overall in China did not increase during the study period despite rapid population aging. Incidence per 100,000 was 180.72 (95% CI 137.16, 224.28; P < 0.001) in 2012 and 177.13 (95% CI 139.93, 214.33; P < 0.001) in 2016 for females, and 121.86 (95% CI 97.30, 146.42; P < 0.001) in 2012 and 99.15 (95% CI 81.31, 116.99; P < 0.001) in 2016 for males. For both sexes, declines in hip fracture incidence were observed in patients aged 65 years and older, although incidence was relatively stable in younger patients. However, the total absolute number of hip fractures in those 55 years and older increased about 4-fold. The total costs for hospitalization showed a steep rise from US$60 million to US$380 million over the study period. Costs for hospitalization per patient increased about 1.59-fold, from US$4,300 in 2012 to US$6,840 in 2016. The main limitation of the study was the unavailability of data on imaging information to adjudicate cases of hip fracture.

Conclusions: Our results show that hip fracture incidence among patients aged 55 and over in China reached a plateau between 2012 and 2016. However, the absolute number of hip fractures and associated medical costs for hospitalization increased rapidly because of population aging.
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http://dx.doi.org/10.1371/journal.pmed.1003180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410202PMC
August 2020

The Effect of Different Types of Mechanical Circulatory Support on Mortality of Patients after Adult Cardiac Surgery: A Systematic Review and Meta-Analysis.

Heart Surg Forum 2020 Jul 27;23(4):E537-E545. Epub 2020 Jul 27.

Shanghai East Hospital, Tongji University, Pudong District, Shanghai, China.

Objectives: Sample size may limit the ability of individual studies to detect differences in clinical outcomes between extracorporeal membrane oxygenation (ECMO) alone and ECMO plus intra-aortic balloon pump (IABP) after adult cardiac surgery. Therefore, we undertook a meta-analysis of the best evidence available on the comparison of clinical outcomes of ECMO alone and ECMO plus IABP after adult cardiac surgery.

Methods: PubMed, EMBASE, Web of Science, and Cochrane Center Registry of Controlled Trials were searched for studies comparing the use of ECMO alone and ECMO plus IABP after adult cardiac surgery. A meta-analysis and a sensitivity analysis were conducted.

Results: Among the 472 screened articles, 24 studies (1302 cases of ECMO plus IABP and 1603 cases of ECMO) were included. A significant relationship between patient risk profile and benefits from IABP plus ECMO was found in terms of the 30-day mortality (odds ratio [OR] 0.75; 95% confidence interval [CI] 0.62 to 0.91; P = .004) with postcardiotomy shock (PCS). However, ECMO alone was associated with lower in-hospital mortality (OR 1.75; 95% CI 1.06 to 3.01; Z = 2.19; P = .03) compared with ECMO plus IABP without PCS.

Conclusions: Pooled data show that patients receiving IABP plus ECMO with PCS have lower 30-day mortality than those receiving ECMO also, which in turn show higher 30-day mortality in patients with IABP plus ECMO without PCS. Further randomized studies are warranted to corroborate these observational data.
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http://dx.doi.org/10.1532/hsf.2979DOI Listing
July 2020

Serum exosomal miR-122-5p is a new biomarker for both acute coronary syndrome and underlying coronary artery stenosis.

Biomarkers 2020 Nov 10;25(7):539-547. Epub 2020 Aug 10.

Department of Cardiology, Second Hospital of Jilin University, Chang Chun, China.

Purpose: Acute coronary syndrome presents as unstable angina (UA) or acute myocardial infarction (AMI). We explored the use of exosomal miR-122-5p as a biomarker for UA and AMI and determined whether its expression level is positively correlated with the severity of coronary stenosis.

Methods: This study enrolled 34 patients with AMI, 31 patients with UA, and 22 control subjects. qPCR was used to detect the expression levels of serum exosomal miR-122-5p.

Results: The expression of serum exosomal miR-122-5p in UA and AMI patients was significantly higher than that in the control group, and expression levels differed between UA and AMI patients. Receiver operating characteristic analysis demonstrated that serum exosomal miR-122-5p might be used as a diagnostic biomarker for AMI and UA. In addition, we also found that serum exosomal miR-122-5p was positively correlated with the severity of coronary artery stenosis for UA patients based on the Gensini score. Serum exosomal miR-122-5p was highly expressed in patients with a coronary artery stenosis severity greater than 80% during acute coronary syndrome.

Conclusion: Serum exosomal miR-122-5p might be useful as a diagnostic biomarker for AMI and UA, and increased serum exosomal miR-122-5p levels could be useful to predict the severity of coronary lesions.
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http://dx.doi.org/10.1080/1354750X.2020.1803963DOI Listing
November 2020

Transfer of microRNA-221 from mesenchymal stem cell-derived extracellular vesicles inhibits atherosclerotic plaque formation.

Transl Res 2020 12 10;226:83-95. Epub 2020 Jul 10.

Department of Cardiovascular Internal Medicine, the Second Hospital of Jilin University, Changchun 130041, P.R. China. Electronic address:

Mesenchymal stem cells (MSCs) have emerged as a cell-based therapy in many diseases including atherosclerosis (AS) due to their capability of immunomodulation and tissue regeneration. However, the pathway for MSCs' antiatherosclerotic activity remains to be elucidated. Here, we test the hypothesis that microRNA-221 (miR-221) from MSC-derived extracellular vesicles (EVs) alleviates AS. Male ApoE mice were fed a high-fat diet for 12 weeks to induce AS, and were then treated with human bone marrow mesenchymal stem cell-derived EVs by tail vein injection. The expression pattern of miR-221 and N-acetyltransferase-1 (NAT1) in AS mice was characterized by quantitative RNA analysis and their interaction was identified by dual-luciferase reporter gene assay. In other studies, human arterial smooth muscle cells treated with oxidized low-density lipoprotein-were co-cultured with MSC-released EVs to evaluate the EV-mediated transfer of miR-221. NAT1 was highly expressed in atherosclerotic lesions. Adenovirus-mediated NAT1 knockdown resulted in a reduced lipid deposition in AS mice. Human bone marrow mesenchymal stem cell -derived EVs carrying miR-221 were internalized by human arterial smooth muscle cells and transferred their miR-221 contents to downregulate the target gene NAT1. Injection of miR-221-containing EVs inhibited lipid deposition in AS mice, in part by downregulating NAT1. The present study provides evidence that miR-221 shuttled by MSC-derived EVs can inhibit atherosclerotic plaque formation in AS model mice, suggesting that miR-221 may serve as a target for improving MSC-based therapeutic strategy against AS.
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http://dx.doi.org/10.1016/j.trsl.2020.07.003DOI Listing
December 2020

Serum Exosomal MicroRNA-21, MicroRNA-126, and PTEN Are Novel Biomarkers for Diagnosis of Acute Coronary Syndrome.

Front Physiol 2020 11;11:654. Epub 2020 Jun 11.

Department of Cardiology, The Second Hospital of Jilin University, Changchun, China.

Acute coronary syndrome (ACS) is a serious threat to public health. Based on clinical manifestations, ACS can be classified into unstable angina (UA) pectoris and acute myocardial infarction (AMI). The purpose of this study was to explore the possibility of using serum exosomal microRNA (miR)-126, miR-21, and phosphatase and tensin homolog (PTEN) expression levels as biomarkers of UA and AMI and to investigate whether these levels were positively correlated with the severity of coronary stenosis based on the Gensini score. Exosomes were isolated by ultracentrifugation from the serum of 34 patients with AMI, 31 patients with UA, and 22 healthy controls. The isolated exosomes were characterized by electron microscopy and particle size analysis; exosomal identity was further confirmed by western blotting using exosome-specific antibodies. Real-time quantitative polymerase chain reaction indicated that the serum exosomal levels of miR-126 and miR-21 were significantly higher in the patients with UA and AMI than in the healthy controls. Enzyme-linked immunosorbent assay showed that the serum exosomal PTEN levels were significantly higher in the UA and AMI groups than in the control group. Receiving operating characteristic curve analysis demonstrated the diagnostic efficiency of serum exosomal miR-126, miR-21, and PTEN levels for predicting AMI and UA. In addition, the circulating exosomal miR-126 level was positively correlated with the severity of coronary artery stenosis in patients with UA and AMI based on the Gensini score.
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http://dx.doi.org/10.3389/fphys.2020.00654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300246PMC
June 2020

A new approach to the treatment of spinal instability: Fusion or structural reinforcement without surgery?

Med Hypotheses 2020 Nov 4;144:109900. Epub 2020 Jun 4.

Department of Orthopedics, Peking University 3rd Hospital, Beijing Key Laboratory of Spinal Disease Research, No. 49 North Garden Rd., Haidian District, Beijing 100191, PR China. Electronic address:

Spinal instability related low back pain is a common condition resulting from degeneration and loss of stiffness of the intervertebral joint. In order to restore stability, highly invasive surgical fusion is needed for patients who are not responding to conservative treatment. Given the risk and complications of surgery, there has been the urge for improvement with a less invasive solution. Formation of vertebral body osteophytes is a common observation that has been treated as a degenerative condition. However, recent studies have associated it with reduced motion of spinal segments. Unlike the traditional view, we regard it as adaptive reactions aiming to repair and hypothesize that the spinal segments could be stabilized or fused by intentionally induced osteophytes growth at the mobile parts of the intervertebral joint. This could be achieved by injecting Bone Morphogenetic Proteins to the anterior ends of the vertebral bodies and/or the facet joints on both sides of two consecutive vertebrae percutaneously. If verified, it would be the first time that fusion could be achieved without surgery. Hence it would provide a valuable alternative to current treatments of spinal instability. Preliminary test in favor of this hypothesis is presented and we recommend that a formal study with sufficient number of samples is needed for verification.
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http://dx.doi.org/10.1016/j.mehy.2020.109900DOI Listing
November 2020