Inactivation of Ihh in Sp7-Expressing Cells Inhibits Osteoblast Proliferation, Differentiation, and Bone Formation, Resulting in a Dwarfism Phenotype with Severe Skeletal Dysplasia in Mice.

Indian hedgehog (Ihh) is an indispensable paracrine factor for proper tissue patterning, skeletogenesis, and cellular proliferation. Recent genetic studies have revealed critical roles of chondrocyte-derived Ihh in regulating chondrocyte proliferation, hypertrophy and cartilage ossification. However, the functions of Sp7-expressing cell-derived Ihh in osteoblast differentiation and bone formation remain unclear. Sp7 is an essential transcription factor for osteoblast differentiation. In the current study, we generated Sp7-iCre; Ihhfl/fl mice, in which the Ihh gene was specifically deleted in Sp7-expressing cells to investigate the roles of Ihh. Ihh ablation in Sp7-expressing cells resulted in a dwarfism phenotype with severe skeletal dysplasia and lethality at birth, but with normal joint segmentation. Sp7-iCre; Ihhfl/fl mice had fewer osteoblasts, almost no cortical and trabecular bones, smaller skulls, and wider cranial sutures. Additionally, the levels of osteogenesis- and angiogenesis-related genes, and of major bone matrix protein genes were significantly reduced. These results demonstrated that Ihh regulates bone formation in Sp7-expressing cells. Ihh deficiency in primary osteoblasts cultured in vitro inhibited their proliferation, differentiation, and mineralization ability, and reduced the expression of osteogenesis-related genes. Moreover, the deletion of Ihh also attenuated the Bmp2/Smad/Runx2 pathway in E18.5 tibial and primary osteoblasts. The activity of primary osteoblasts in mutant mice was rescued after treatment with rhBMP2. In summary, our data revealed that Ihh in Sp7-expressing cells plays an indispensable role in osteoblast differentiation, mineralization, and embryonic osteogenesis, further implicated that its pro-osteogenic role may be mediated through the canonical Bmp2/Smad/Runx2 pathway.

The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy.

Purpose: To determine the role of histone deacetylase 4 (HDAC4)-controlled chondrocyte hypertrophy in the onset and development of age-related osteoarthritis (OA). Methods: Morphological analysis of human knee cartilages was performed to observe structural changes during cartilage degeneration. HDAC4 expression was deleted in adult aggrecan (Acan)-CreERT2; HDAC4fl/fl transgenic mice. The onset and development of age-related OA were investigated in transgenic and control mice using hematoxylin and eosin (H&E) and Safranin O staining. Furthermore, the progression of ACLT-induced OA following adenovirus-mediated HDAC4 overexpression was explored in rats. The expression levels of genes related to hypertrophy, cartilage matrix and its digestion, and chondrocyte proliferation were investigated using qPCR. Immunohistochemistry (IHC) was used to explore the mechanisms underlying HDAC4-controlled age-related changes in OA progression. Results: In human cartilage, we performed morphological analysis and IHC, the results showed that hypertrophy-related structural changes are related to HDAC4 expression. Age-related OA was detected early (OARSI scores 2.7 at 8-month-old) following HDAC4 deletion in 2-month-old mice. Furthermore, qPCR and IHC results showed changes in hypertrophy-related genes Col10a1, Runx2 and Sox9 in chondrocytes, particularly in the expression of Runt-related transcription factor 2 (Runx2, 13.29±0.99 fold). The expression of the main cartilage matrix-related genes Col2a1 and Acan decreased, that of cartilage matrix digestion-related gene MMP-13 increased, while that of chondrocyte proliferation-related genes PTHrP, Ihh and Gli1 changed. In contrast, rat cartilage's qPCR and IHC results showed opposite outcomes after HDAC4 overexpression. Conclusion: Based on the results above, we concluded that HDAC4 expression regulates the onset and development of age-related OA by controlling chondrocyte hypertrophy. These results may help in the development of early diagnosis and treatment of age-related OA.

[META analysis of mobile bearing and fixed bearing unicondyle replacement for medial knee osteoarthritis].

OBJECTIVE: To evaluate of the clinical effects of mobile-bearing(MB) and fixed-bearing(FB) unicompartmental knee arthroplasty(UKA) in the treatment of knee osteoarthritis by Meta-analysis. METHODS: The literature on FB UKA and MB UKA in the treatment of knee osteoarthritis in PubMed, CNKI, Wanfang, Cochrane and EMBASE database were searched by computer from January 2000 to April 2020. According to the inclusion and exclusion criteria, two authors were selected independently and the selected literature was evaluated for quality.After literature data were extracted, Review Manager 5.3 software was used to analyze knee function score, postoperative activity, revision rate, polyethylene wear rate, pad dislocation, aseptic loosening, postoperative pain, knee arthritis progression, mechanical shaft alignment of lower limbs, and imaging clarity line respectively. RESULTS: A total of 13 literatures were included in this meta-analysis, including 2 randomized controlled studies and 11 cohort studies. A total of 1 871 patients were included, including 913 in FB UKA group and 958 in MB UKA group. Meta analysis results showed that:postoperative knee joint function score[MD=-0.84, 95%CI(-1.46, -0.21), P=0.008] and postoperative knee joint range of motion [MD=-1.51, 95%CI(-2.84, -0.18), P=0.03] in FB UKA group were better than those in MB UKA group. Compared with FB UKA group, MB UKA group had a higher lower limb mechanical axis alignment rate[OR=2.08, 95%CI(1.27, 3.39), P=0.003], and the wear rate of polyethylene [OR=0.11, 95%CI(0.01, 0.91), P=0.04] was lower. There were no differences between two groups in the renovation rate [OR=1.16, 95%CI(0.75, 1.80), P=0.50), liner dislocation rate[OR=3.78, 95%CI(0.93, 15.29), P=0.06], aseptic loosening [OR=2.11, 95%CI(0.81, 5.51), P=0.13], postoperative pain[OR=1.13, 95%CI(0.37, 3.43), P=0.83], osteoarthritis progression[OR=1.28, 95%CI(0.67, 2.47), P=0.46)and imaging radiolucent line[OR=1.62, 95%CI(0.09, 30.22), P=0.75]. CONCLUSION: FB UKA has a higher postoperative functional score and range of motion.MB UKA has more advantages in the correction of lower limb mechanical axis, and the wear rate of polyethylene is also lower. There was no significant difference between the two groups in revision rate, dislocation of the liner, aseptic loosening, postoperative pain, progression of osteoarthritis, and postoperative translucency.

Inflammatory factors are crucial for the pathogenesis of post-traumatic osteoarthritis confirmed by a novel porcine model: "Idealized" anterior cruciate ligament reconstruction" and gait analysis.

OBJECTIVE: To determine whether idealized anterior cruciate ligament reconstruction (IACL-R) restores normal gait features, and whether inflammatory factors are involved in the pathogenesisof post-traumatic osteoarthritis (PTOA). METHODS: Fourteen mature female minipigs were allocated to a sham group (n = 7) or an IACL-R group (n = 7). Load asymmetry during gait was recorded using a pressure-sensing walkway measurement system to evaluate the gait features of the right knee joint before and after surgery. Inflammatory factors (including interleukin [IL]-1α, IL-1ß, IL-2, IL-6, IL-8, IL-18, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor) in synovial fluid were measured using Luminex assays before and after surgery. Cartilage integrity and the subchondral bone plate of the right knee were evaluated using histology and imaging at 3 months postoperatively. RESULTS: Swing time and stance time returned to their preoperative values on day 31, while maximum force, contact area, peak force ,and impulse returned to their preoperative values on day 45 after the surgery in the IACL-R group (P = 0.073, 0.053, 0.107, 0.052, 0.152, and 0.059, respectively).Thus, IACL-R restored normal gait. Compared with their preoperative concentrations, all tested inflammatory factors showed significantly increased concentrations in the synovial fluid in the IACL-R group, especially at 3, 7, and 15 days postoperatively. X-ray, computed tomography, magnetic resonance imaging, and histological data showed severe cartilage damage in the IACL-R model. CONCLUSION: IACL-R restored normal gait features but caused significant cartilage damage, indicating that significantly elevated inflammatory factors maybe crucial for the pathogenesis of PTOA.

Studies of Articular Cartilage Repair from 2009 to 2018: A Bibliometric Analysis of Articles.

OBJECTIVE: To perform a bibliometric analysis of research on articular cartilage repair published in Chinese and English over the past decade. Fundamental and clinical research topics of high interest were further comparatively analyzed. METHODS: Relevant studies published from 1 January 2009 to 31 December 2018 (10 years) were retrieved from the Wanfang database (Chinese articles) and six databases, including MEDLINE, WOS, INSPEC, SCIELO, KJD, and RSCI on the website "Web of Science" (English articles), using key words: "articular cartilage" AND "injury" AND "repair". The articles were categorized according to research focuses for a comparative analysis between those published in Chinese vs English, and further grouped according to publication date (before and after 2014). A comparative analysis was performed on research focus to characterize the variation in research trends between two 5-year time spans. Moreover, articles were classified as basic and clinical research studies. RESULTS: Overall, 5762 articles were retrieved, including 2748 in domestic Chinese journals and 3014 in international English journals. A total of 4937 articles focused on the top 10 research topics, with the top 3 being stem cells (32.1%), tissue-engineered scaffold (22.8%), and molecular mechanisms (16.4%). Differences between the numbers of Chinese and English papers were observed for 3 topics: chondrocyte implantation (104 vs 316), osteochondral allograft (27 vs 86), and microfracture (127 vs 293). The following topics gained more research interest in the second 5-year time span compared with the first: microfracture, osteochondral allograft, osteochondral autograft, stem cells, and tissue-engineered scaffold. Articles with a focus on three-dimensional-printing technology have shown the fastest increase in publication numbers. Among 5613 research articles, basic research studies accounted for the majority (4429), with clinical studies described in only 1184 articles. The top 7 research topics of clinical studies were: chondrocyte implantation (28.7%), stem cells (21.9%), microfracture (19.2%), tissue scaffold (10.6%), osteochondral autograft (10.5%), osteochondral allograft (6.3%), and periosteal transplantation (2.8%). CONCLUSION: Studies focused on stem cells and tissue-engineered scaffolds led the field of damaged articular cartilage repair. International researchers studied allograft-related implantation approaches more often than Chinese researchers. Traditional surgical techniques, such as microfracture and osteochondral transplantation, gained high research interest over the past decade.

Correlates of recent HIV infection among men who have sex with men recruited through the internet in Huzhou City, Eastern China.

OBJECTIVE: To identify factors associated with recent HIV infection among men who have sex with men (MSM) in Huzhou City, Eastern China, who seek sexual partners via the internet. METHODS: Adult members of Tencent QQ instant messaging software, who completed a face-to-face interview questionnaire and serological HIV testing at baseline, were enrolled into this prospective cohort study. Questionnaires and serological testing were also completed at 6 and 12 months. Cox proportional hazards was used for initial bivariate analyses of differences between participants with or without recent HIV infection, and for subsequent forward stepwise multiple regression of statistically significant variables. RESULTS: Out of 415 baseline participants, 283 completed the 12-month follow-up (25 with recent HIV infection and 258 without; recent HIV infection rate, 8.20 per 100 person-years). Recent HIV infection was shown to be significantly associated with ≤ high school education (versus college/university), registered residence outside Huzhou City (versus within Huzhou City), having ≥ two male sexual partners, and syphilis infection. CONCLUSIONS: Improving education levels, treating syphilis promptly, and reducing the number of male sexual partners may reduce HIV transmission among MSM in Eastern China.

Risk Factors for HIV Diagnosis Among Men Who Have Sex with Men: Results of a Case-Control Study in One Sample of Eastern China.

Substantial increases in human immunodeficiency virus (HIV) have been reported worldwide in recent years, particularly among men who have sex with men (MSM). We conducted a matched case-control study to examine the factors associated with HIV diagnosis among MSM in one sample of eastern China. Between February 2012 and December 2014, we used surveillance records to identify MSM diagnosed with HIV (case participants); we also recruited MSM who did not have HIV (controls) and then matched them (2:1) with control cases in terms of age (±3 years). Multivariate logistic regression models were used to assess the factors associated with HIV diagnosis. According to a multivariate analysis using logistic regression model involving 101 cases and 202 matched controls, a lack of comprehensive knowledge of HIV (adjusted odds ratio [OR] = 0.40; 95% confidence interval [CI] = 0.18, 0.89), a monthly income of ≥4,000 RMB (adjusted OR = 2.99; 95% CI = 1.45, 6.16), having at least two male sexual partners in the past 6 months (adjusted OR = 2.85; 95% CI = 1.28, 6.31), participating in at least four anal sex experiences with a man in the past month (adjusted OR = 3.56; 95% CI = 1.64, 7.73), and having a current syphilis infection (adjusted OR = 3.30; 95% CI = 1.06, 10.25) were associated with an increased risk for HIV diagnosis. MSM with a comprehensive knowledge of HIV were at reduced risk of HIV diagnosis, whereas those with more male sexual partners, more male anal sexual experiences (including receptive or/and insertive anal intercourse, rimming, and fisting), and a current syphilis infection were at increased risk of HIV diagnosis. Focus on protection and safer sex behaviors during male sexual activity (i.e., consistent condom use, pre-exposure prophylaxis, closed sexual networks among MSM) would likely be effective for reducing the HIV transmission rate.

Prevalence of high-risky behaviors in transmission of HIV among high school and college student MSM in China: a meta-analysis.

BACKGROUND: The aim of this study was to investigate the prevalence of high-risky behaviors, such as unprotected anal intercourse (UAI) in the last 6 months, condom using in their last homosexual anal intercourse, No. of male partners in the last 6 months among high school and college male students who have sex with men (MSM) in China. METHODS: The relevant trials were retrieved up to June 2015 from several public databases, and a meta-analysis was conducted according to the published studies. The estimated rate and its 95 % confidence intervals (CI) of the relevant indexes among high school and college student MSM were collected and calculated using a fixed-effects model (the Mantel-Haenszel method) or a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS: A total of 15 studies (18 research data), including 3297 student MSM, were performed in this meta-analysis. The overall results showed that the rate of student MSM who reported having had UAI in the last 6 months was 65.2 % (95 % CI = 60.2 % to 70.1 %), the prevalence of student MSM having more than one male partner in the last 6 months was 58.2 % (95 % CI = 51.1 % to 65.4 %), the rate of student MSM who reported using a condom in their last homosexual anal intercourse experience was 57.5 % (95 % CI = 49.8 % to 65.1 %), the prevalence of student MSM who were infected with HIV was 3.8 % (95 % CI = 2.5 % to 5.1 %), and the rate of student MSM who were infected with syphilis was 4.6 % (95 % CI = 3.8 % to 5.4 %). CONCLUSIONS: There are high UAI prevalence and low condom using rate in the last homosexual anal intercourse experience among high school and college student MSM in China, and corresponding control measures for this group and more effective health education of student MSM are required to prevent HIV or sexually transmitted diseases from spreading to the general population.

The Uptake of Prevention of Mother-to-Child HIV Transmission Programs in China: A Systematic Review and Meta-Analysis.

BACKGROUND: No systematic review of prevention of mother to child transmission (PMTCT) in China has been performed. We aimed to estimate the uptake of PMTCT programs services in China. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang (Chinese) to identify research studies. Only descriptive epidemiological studies were eligible for this study. RESULTS: A total of 57 eligible cross-section studies were finally included. We estimated that the mean HIV-positive rate of exposed infants was 4.4% (95% CI = 3.2-5.5), and more than 33% of exposed infants had not undergone HIV diagnostic testing. The percentage of initiating antiretroviral therapy (ART) in HIV-positive women was 71.0% (95% CI = 66.3-75.8), and that for initiating antiretroviral prophylaxis (ARP) in exposed infants was 78.3% (95% CI = 74.9-81.8); also, 31.3% (95% CI = 15.5-47.0) of women with HIV and < 1% of exposed infants received the combination of three antiretroviral drugs. There were bigger gap of uptake of PMTCT programs between income levels, and cities with a low income level had a higher percentage of initiating ART in HIV-positive women (80%) and ARP in exposed infants (85%) compared to cities with high-middle income (57% and 65%, respectively) (P<0.05). CONCLUSIONS: This paper highlights the need to further scale up PMTCT services in China, especially in regions with the lowest coverage, so that more women can access and utilize them. However, some estimated outcome should be interpreted with caution due to the high level of heterogeneity and the small number of studies.

Prevalence of unprotected anal intercourse in men who have sex with men recruited online versus offline: a meta-analysis.

BACKGROUND: Men who have sex with men (MSM) are a high risk population for human immunodeficiency virus (HIV) infection. Our study aims to find whether MSM who were recruited online had a higher prevalence of self-reported unprotected anal intercourse (UAI) than those who were recruited offline. METHODS: A meta-analysis was conducted from the results of published studies. The analysis was stratified by the participants' geographic location, the sample size and the date of the last reported UAI. RESULTS: Based on fourteen studies, MSM who were recruited online (online-based group) reported that 33.9% (5,961/17,580) of them had UAI versus 24.9% (2,700/10,853) of MSM who were recruited offline (offline-based group). The results showed that it is more likely for an online-based MSM group to have UAI with male partners than an offline-based MSM group [odds ratio (OR) = 1.35, 95% CI = 1.13-1.62, P < 0.01]. The subgroup analysis results also showed that the prevalence of UAI was higher in the European subsample (OR = 1.38, 95% CI = 1.17-1.63, P < 0.01) and in sample sizes of more than 500 individuals (OR = 1.32, 95% CI = 1.09-1.61, P < 0.01) in the online group compared to the offline group. The prevalence of UAI was also significantly higher when the time of the last UAI was during the last 3 or more months (OR = 1.40, 95% CI = 1.13-1.74, P < 0.05) in the online group compared to the offline group. A sensitivity analysis was used to test the reliability of the results, and it reported that the results remained unchanged and had the same estimates after deleting any one of the included studies. CONCLUSIONS: A substantial percentage of MSM were recruited online, and they were more inclined to engage in UAI than MSM who were recruited offline. Targeted interventions of HIV prevention programs or services are recommended when designing preventive interventions to be delivered via the Internet.

Correlates of consistent condom use among men who have sex with men recruited through the Internet in Huzhou city: a cross-sectional survey.

BACKGROUND: There is growing evidence that men who have sex with men (MSM) are currently a group at high risk of HIV infection in China. Our study aims to know the factors affecting consistent condom use among MSM recruited through the internet in Huzhou city. METHODS: An anonymous cross-sectional study was conducted by recruiting 410 MSM living in Huzhou city via the Internet. The socio-demographic profiles (age, education level, employment status, etc.) and sexual risk behaviors of the respondents were investigated. Bivariate logistic regression analyses were performed to compare the differences between consistent condom users and inconsistent condom users. Variables with significant bivariate between groups' differences were used as candidate variables in a stepwise multivariate logistic regression model. All statistical analyses were performed using SPSS for Windows 17.0, and a p value < 0.05 was considered to be statistically significant. RESULTS: According to their condom use, sixty-eight respondents were classified into two groups. One is consistent condom users, and the other is inconsistent condom users. Multivariate logistic regression showed that respondents who had a comprehensive knowledge of HIV (OR = 4.08, 95% CI: 1.85-8.99), who had sex with male sex workers (OR = 15.30, 95% CI: 5.89-39.75) and who had not drunk alcohol before sex (OR = 3.10, 95% CI: 1.38-6.95) were more likely to be consistent condom users. CONCLUSIONS: Consistent condom use among MSM was associated with comprehensive knowledge of HIV and a lack of alcohol use before sexual contact. As a result, reducing alcohol consumption and enhancing education regarding the risks of HIV among sexually active MSM would be effective in preventing of HIV transmission.

[Prevalence of HIV among men who have sex with men of inland high school and college students in China: a meta-analysis].

OBJECTIVE: To analyze the prevalence of HIV among men who have sex with men (MSM) of inland high school and college students in China, and to analyze the differences between sample size, sampling methods and study period. METHODS: Electronic search strategy was carried out, using WanFang database, China Journal Full-text database, VIP database, CBM and PubMed database to collect data on high school and college students, HIV and MSM, among residents in China. Fixed effects model or random effects model was employed according to statistical tests for homogeneity. Publication bias was assessed by funnel plot. RESULTS: Ten studies were selected with a total of 2014 students-MSM and 106 HIV infected. The overall prevalence of HIV was 4.6% (95% CI 2.9%-6.3%). The prevalence of HIV was stratified by factors as sample size, sampling methods and study period of the study. The pooled prevalence rates of HIV were as follows: 4.7% (95% CI 2.5%-7.0%) and 4.7% (95% CI 1.9%-7.4%) for sample size > 200 and sample size 200, 6.1% (95% CI 3.0%-9.1%) and 2.9% (95% CI 1.7%-4.1%) for snow sampling and non-snow sampling, respectively. The pooled prevalence of HIV were 3.0% (95% CI 1.7%-4.2%) in the study year of 2005-2007 and 6.0% (95% CI 3.1%-9.0%) in 2008-2010, respectively. The pooled prevalence of HIV was higher in snow sampling than non-snow sampling, in the study year of in 2008-2010 than in 2005-2007. CONCLUSION: The prevalence of HIV among MSM of inland high school and college students in China was higher than general population.