Teriparatide prevented synovial inflammation and cartilage destruction in mice with DMM.

AIM: Emerging data have demonstrated that low-grade inflammation in osteoarthritis, a long-held degenerative disease. The inflamed synovium produces various cytokines that induce cartilage destruction and joint pain. A previous study showed that teriparatide, an FDA approved anti-osteoporotic drug, may enhance cartilage repair. Our study focuses on its role in OA synovitis. MATERIALS AND METHODS: Primary mouse articular chondrocytes were used to determine the most potent cytokines involved in OA inflammation and cartilage destruction. A destabilization of the medial meniscus mouse model was established to investigate the effect of teriparatide in OA, particularly, on synovial inflammation and cartilage degradation. RESULTS: In vitro experiments showed that TNF-α was the most potent inducer of cartilage matrix-degrading enzymes, and that teriparatide antagonized the TNF-α of effect. Consistently, articular cartilage samples from TNF-α transgenic mice contained more MMP-13 positive chondrocytes than those from wild type mice. In addition, more type II collagen was cleaved in human OA cartilage than in normal cartilage samples. CONCLUSIONS: Teriparatide can prevent synovitis and cartilage degradation by suppressing TNF-α mediated MMP-13 overexpression. Together with its chondroregenerative capability, teriparatide may be the first effective disease modifying osteoarthritis drug.

Clinical features and independent predictors of Behçet's disease associated with myelodysplastic syndrome.

OBJECTIVES: To investigate the correlation of Behçet's disease (BD) with myelodysplastic syndrome (MDS) and identify the predictive risk factors in Chinese patients. METHODS: A retrospective study of BD associated with MDS (BD-MDS) patients from the First Affiliated Hospital of Zhengzhou University was conducted. RESULTS: Among 15 BD-MDS patients, 10 were females and 5 males. While 13 (86.7%) patients had abnormal karyotype, 11 patients with trisomy 8. 10 (66.7%) had gastrointestinal (GI) involvement. Compared with 60 general BD patients without MDS, the BD-MDS patients were significantly older. In addition, fever and GI involvement were more common in BD-MDS patients, whereas these patients had lower levels of leukocyte count, haemoglobin, and platelet count (p<0.05). Logistic regression analysis showed that GI involvement, low haemoglobin, and high ESR level were independently associated with the development of MDS in BD patients. BD-MDS patients with GI involvement (IBD-MDS) were usually much older and have more fever than IBD patients without MDS, as well as lower leukocyte count, haemoglobin level, platelet count, and higher erythrocyte sedimentation rate (ESR) and C-reactive protein levels (p<0.05). By comparison with 60 primary MDS patients without BD, the BD-MDS patients had more abnormal karyotypes and more trisomy 8 (p<0.05), while the distribution of 2016 WHO subtypes of MDS and IPSS-R categories were similar. CONCLUSIONS: Our findings suggest that cytogenetic abnormalities, especially trisomy 8, may play a role in the association of GI involvement, BD, and MDS. GI involvement, low haemoglobin, and high ESR level were independent predictors for MDS development in BD patients.

Intravenous immunoglobulin for interstitial lung diseases of anti-melanoma differentiation-associated gene 5-positive dermatomyositis.

OBJECTIVE: Rapidly progressive interstitial lung disease (RP-ILD) in DM patients positive for anti-melanoma differentiation-associated gene 5 (anti-MDA5) autoantibody (MDA5-DM) often have a poor prognosis, frequently fatal. As there is a scarcity of data regarding the effect of intravenous immunoglobulin (IVIG) on RP-ILD in MDA5-DM patients (MDA5-RPILD), we conducted this study to determine the efficacy of a IVIG add-on initial treatment. METHODS: Patients with newly-onset MDA5-RPILD from September 2018 to June 2020 were retrospectively reviewed for 6 months in the First Affiliated Hospital of Zhengzhou University. They were divided into two groups: IVIG and non-IVIG groups. The major measurement of treatment outcome was the difference in the mortality in 3-month and 6-month between two group patients. Other relevant indicators were also recorded, including the incidence of infection, the dosages of GCs, the remission rate and the variables in laboratory data. RESULTS: The IVIG group (n = 31) showed significantly lower 6-month mortality rate than the non-IVIG group (n = 17) (22.6% vs 52.9%; P =0.033). The IVIG group patients had a higher remission rate at 3 months (71.0% vs 41.2%; P =0.044). Gradual reduction was observed in the first 3 months with regard to the titre of anti-MDA5 autoantibody, the serum level of ferritin and the ground glass opacification GGO scores. CONCLUSION: IVIG adjunct therapy is a very effective first-line treatment for patients with MDA5-RPILD. IVIG may increase the survival and remission rate by lowering ferritin concentration, anti-MDA5 titre and GGO score.

ATF4-modified serum exosomes derived from osteoarthritic mice inhibit osteoarthritis by inducing autophagy.

Activating transcription factor 4 (ATF4) is critical for chondrocyte proliferation and bone formation. Exosomes are considered as promising gene-delivery vehicles for the treatment of osteoarthritis (OA). This study utilized the serum-derived exosomes from OA mice as the gene-delivery vehicles for ATF4 gene therapy and explored their therapeutic effects on OA. Meniscus injury-induced OA model was established by the excision of anterior part of medial meniscus in the right knee of C57BL/6J mice. Exosomes were isolated from serum samples of sham and OA mice, and were referred to as sham-Exo and OA-Exo, respectively. ATF4-overexpressing OA-Exo (ATF4-OA-Exo) was developed by introducing ATF4 mRNA into OA-Exo via electroporation. Four weeks after surgery, OA mice received intra-articular injections of sham-Exo, OA-Exo, and ATF4-OA-Exo, respectively. The results showed that intra-articular injection of ATF4-OA-Exo alleviated articular cartilage degeneration or damage and inflammatory response of OA mice. Autophagy was weakened in knee joint cartilage of OA mice, which was partially restored by intra-articular injection of ATF4-OA-Exo. Further in vitro assays revealed that ATF4-OA-Exo promoted chondrocyte autophagy and inhibited chondrocyte apoptosis in the TNF-α- or tunicamycin-treated chondrocytes. Together, ATF4-modified serum exosomes derived from OA mice protect cartilage and alleviate OA progression by inducing autophagy.

Forskolin attenuates the NLRP3 inflammasome activation and IL-1ß secretion in human macrophages.

BACKGROUND: The treatment of nucleotide-binding domain and leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome-mediated pediatric inflammatory diseases is challenging. Here we studied whether cyclic adenosine monophosphate (cAMP) elevator forskolin could attenuate the nigericin-induced NLRP3-inflammasome activation and interleukin-1ß (IL-1ß) secretion in human macrophages. METHODS: The proteins and messenger RNA (mRNA) levels of inflammasome structural proteins and proinflammatory cytokines were measured in forskolin-stimulated nigericin-activated human THP-1 macrophages and primary macrophages. RESULTS: Activation of THP-1 macrophages with nigericin increased the mRNA expression of NLRP3, IL-1ß, and caspase-1 (P < 0.01). Forskolin stimulation had no effect on the mRNA expression of NLRP3, caspase-1, or IL-1ß in nigericin-activated cells (P > 0.05), while their protein levels were significantly decreased (P < 0.05). Forskolin-mediated increase in cytoplasmic cAMP in non-activated cells was attenuated in nigericin-activated macrophages (P < 0.05). Basal IL-1ß secretion increased from 584 to 2696 pg/mL (P < 0.01) in nigericin-activated macrophages; forskolin dose-dependently reduced the nigericin-induced secretion of mature IL-1ß (P < 0.01). Forskolin also inhibited the IL-1ß secretion from activated human primary macrophages. CONCLUSIONS: Forskolin inhibits the NLRP3 inflammasome activation and the secretion of mature IL-1ß, in human macrophages. Forskolin and other cAMP elevator drugs could represent a novel approach for treatment of diseases associated with excessive inflammasome activation, like pediatric inflammatory diseases.

Predictive factors and prognosis of macrophage activation syndrome associated with adult-onset Still's disease.

OBJECTIVES: To summarise the clinical data of adult-onset Still's disease (AOSD) patients and analyse their clinical manifestations, predictors for the formation and prognosis of macrophage activation syndrome (MAS). METHODS: A retrospective analysis was performed on the clinical data of 182 AOSD hospitalised patients from the Department of Rheumatology of the First Affiliated Hospital of Zhengzhou University, China from January 2012 to August 2018, including 11 patients with pathogenesis of MAS. RESULTS: Compared with the patients without MAS, the patients with MAS had a higher incidence of splenomegaly and pericarditis at the initial diagnosis of AOSD. The number of platelets (PLT) and the concentration of fibrinogen (FIB), D-Dimer and ferritin were significantly higher in AOSD-MAS patients. Multivariate regression analysis showed that splenomegaly (OR: 5.748, 95% CI: 1.378-23.984, p=0.016), pericarditis (OR: 6.492, 95% CI: 1.43-29.461, p=0.015), and ferritin >2000 µg/L (OR: 4.715, 95% CI: 1.12-19.86, p=0.035) were risk factors for MAS. Survival analysis indicated that the mortality of AOSD-MAS patients was significantly higher than patients without MAS. CONCLUSIONS: Splenomegaly, pericarditis and elevated ferritin concentration are risk factors for MAS formation in AOSD patients. MAS resulted in a significant decrease in the survival rate of the AOSD patients.

The influence of delay elimination communication on the prevalence of primary nocturnal enuresis-a survey from Mainland China.

AIMS: A pilot survey shows that primary nocturnal enuresis (PNE) prevalence has increased significantly during the past decade in Mainland China. Whether it is related to the delay of elimination communication (EC) is unclear. This study retrospectively investigated the influence of delayed EC on the PNE prevalence in children and adolescents in mainland China. METHODS: A cross-sectional study of PNE prevalence was performed by distributing 19 500 anonymous self-administered questionnaires to parents in five provinces of mainland China from July 2017 to October 2017. The questionnaires included sociodemographic data, family caregivers' information, and details about the disposable diapers (DD) usage, EC commencement date, psychological disorders, lower urinary tract symptoms, and family history of PNE in children and adolescents. The 2017 PNE prevalence was compared with that of 2006 in Mainland China. RESULTS: The total response rate was 97.04% (18 631 of 19 500) and 92.39% (18 016 of 19 500) qualified for statistical analysis. The PNE prevalence in 2017 has increased significantly compared to that of 2006 (7.30% vs 4.07%, P < 0.001). The PNE prevalence in children with EC starting before 6 months of age was significantly lower than those who start after 12 months of age. The longer DD were used and the later the beginning of EC, the higher the PNE prevalence was found. CONCLUSIONS: The PNE prevalence in Mainland China has increased significantly during the past 10 years. A longer use of DD and later onset of EC may be risk factors for PNE.

Generation of regulable EGFRvIII targeted chimeric antigen receptor T cells for adoptive cell therapy of glioblastoma.

Adoptive immunotherapy using chimeric antigen receptors-modified T cells (CAR-T) is a promising approach for cancer treatment. However, CARs currently applied in the clinics cannot be effectively regulated and the safety of CAR-T cell therapies remains a major concern. To improve the safety of CAR-T cells, we designed a synthetic splitting CAR (ssCAR) that can regulate T cell functions exogenously. Epidermal growth factor receptor variant III (EGFRvIII) was used as a molecular target for ssCAR. Our results indicate that both EGFRvIII and small molecule are needed for the activation of the ssCAR-T cells. AP21967 dose-dependently increased the expression of T cell activation, production of cytokines and extent of cell lysis. In conclusion, the gene switch designed in this study allows for temporal and spatial control over engineered T cells in a dose-and time-dependent manner by AP21967. Our work demonstrates the feasibility and improved safety profile of this novel treatment approach.

Neutrophils produce interleukin-17B in rheumatoid synovial tissue.

OBJECTIVE: T helper 17 (Th17) and mast cells produce IL-17A in RA and critically contribute to the pathogenesis of RA. However, the complete IL-17 cytokine profile in RA is unknown. The aim of the study was to systematically study the expression of IL-17 family cytokines in RA. METHODS: The expression of all IL-17 cytokines in RA synovium and pannus as well as in the synovium of OA was determined using quantitative RT-PCR (qRT-PCR). IL-17A and IL-17B were immunostained. Peripheral blood neutrophils were analysed for IL-17B. The effect of IL-17B alone or in combination with TNF-α was tested in vitro on fibroblasts and endothelial cells. RESULTS: In all tissues IL-17B was the most expressed IL-17 family cytokine, found in lining but most strongly expressed in human neutrophil elastase containing polymorphonuclear cells. This pattern was distinct from that of IL-17A, which was found in mast cell tryptase immunoreactive cells. Circulating neutrophils contained IL-17B, verifying the in vivo results. Fibroblasts up-regulated the expression of IL-17RB, a putative receptor of IL-17B, after TNF-α stimulation. IL-17B significantly enhanced TNF-α-induced production of G-CSF and IL-6 in fibroblasts. CONCLUSION: IL-17B, which is present in synovium, may contribute to the pathogenesis of RA. IL-17B can enhance the effects of TNF-α on the production of cytokines and chemokines that control immune cell trafficking and neutrophil homeostasis in the inflamed tissues.

Investigative biological therapies for primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by dryness of the eyes and mouth. The histological feature is mononuclear cell infiltration in exocrine glands, primarily salivary and lachrymal glands. As the disease progresses, some other tissues and organs may be involved and extraglandular manifestations ensue. The major current treatments are palliative and empirical, and in most cases the outcomes are not satisfactory. Emerging data indicate a critical role of lymphocytes in its development and progression. While pioneering work targeting B cells has demonstrated some encouraging results, more trials are warranted to validate the safety and efficacy. In addition, modulation of T cell function with abatacept ameliorates the severity of pSS. Furthermore, clinical trials to inhibit important cytokines involved in its formation have been carried out. In this article, we summarize and compare current biological therapies in order to find new and effective treatments for pSS.

Inhibition of the Wnt-ß-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy.

Osteosarcoma (OS) is one of the most common malignant bone tumors in early adolescence. Multi-drug chemotherapy has greatly increased the five year survival rate from 20% to 70%. However, the rate has been staggering for 30 years and the prognosis is particularly poor for patients with recurrence and metastasis. Our study aimed to investigate the role of Wnt-ß-catenin, Notch and Hedgehog pathway in OS development because all these pathways are involved in skeletal development, tumorigenesis and chemoresistance. Our results showed that the major components in Wnt-ß-catenin pathway, e.g. Wnt3a, ß-catenin and Lef1, were consistently upregulated in human osteosarcoma cell line Saos2 cells compared to human fetal osteoblasts (hFOB), whereas the changes in the expression levels of Notch and Hh signaling molecules were not consistent. Knocking down ß-catenin increased the Saos2 sensitivity to methotrexate (MTX) induced cell death. Consistently, the expression level of ß-catenin protein correlated with the invasiveness of OS, as evidenced by more intensive ß-catenin immunoreactivity in higher grade OS samples. Chemical inhibition of the Wnt-ß-catenin signaling enhanced MTX mediated death of Saos2 cells. A synergistic effect with MTX was observed when both inhibitors for Wnt-ß-catenin and Notch pathways were simultaneously used, while the addition of the Hh inhibitor did not further improve the efficacy. Our findings provide some novel insight to OS pathogenesis and lay a foundation for future application of Wnt-ß-catenin and Notch inhibitors together with the currently used chemotherapeutic drugs to improve the outcome of OS treatment.

Exploring the Association Between History of Psoriasis (PSO) and Disease Activity in Patients with Psoriatic Arthritis (PsA).

INTRODUCTION: Psoriatic arthritis (PsA) is a common inflammatory disease affecting the peripheral and axial skeleton. History of psoriasis (PSO), either personal or family history, is an important factor in the diagnosis of PsA. We investigated the association between history of PSO and clinical characteristics of PsA. METHODS: PsA patients were consecutive recruited from 2019 to 2020. These patients were subjected to clinical, biochemical, and radiographic examinations, and disease activity was evaluated. Continuous and categorical variables analyses were presented. RESULTS: All registered patients (296 cases) met the classification criteria of PsA. They were divided into three groups based on the history of psoriasis (PSO), as: (1) 145 patients with PSO themselves (pPsA); (2) 96 patients with family history of PSO (fPsA); (3) 55 patients with family history and coexisting PSO themselves (fPsA/PSO). Compared to fPsA/PSO, the levels of CRP, ESR, uric acid, DAPSA, BASDAI, ASDAS, and BASFI were lower in fPsA, but similar to pPsA. The severity of sacroiliitis tended to be more severe in fPsA/PSO than fPsA (OR2 vs. 3 0.508; 95% CI 0.272 to 0.949, p < 0.05). No significant differences were found in HLA-B-27 and common inflammatory articular and extra-articular manifestations among the three groups. Furthermore, there were no differences in LEI, TJC, SJC, and DAS28CRP. Interestingly, a correlation was found between the ages of individuals with PSO and the onset of arthritis, and the earliest arthritis onset occurred in fPsA/PSO patients (p < 0.001). CONCLUSIONS: Our study demonstrates that currently existing cutaneous lesions in patients themselves are correlated with disease activity and severity of axial joint damage, whereas family history does not have an evident impact on the disease activity of PsA.

Dactylitis Is Associated With More Severe Axial Joint Damage and Higher Disease Activity in Axial Psoriatic Arthritis.

OBJECTIVE: To investigate the association of dactylitis with disease activity and the severity of damage detected by radiography in patients with axial psoriatic arthritis (axPsA). METHODS: Patients with axPsA who met the Classification Criteria for Psoriatic Arthritis were recruited. Clinical data, radiographic changes, and disease activity in patients with axPsA with or without dactylitis were compared using t tests, Mann-Whitney U tests, or Kruskal-Wallis tests for continuous variables. Chi-square or Fisher exact tests were used for categorical variables, and logistic regression analysis was performed to evaluate the association between dactylitis and damage detected by radiography. RESULTS: A total of 186 patients with axPsA were analyzed and dichotomized according to the presence or absence of dactylitis. Patients with dactylitis, as compared to those without dactylitis, had higher C-reactive protein (P = 0.004), erythrocyte sedimentation rate (P = 0.006), neutrophil-to-lymphocyte ratio (P = 0.04), and platelet-to-lymphocyte ratio (P = 0.02). In addition, patients with dactylitic axPsA, as compared to patients with nondactylitic axPsA, had higher tender joint counts, swollen joint counts, Disease Activity Index for Psoriatic Arthritis (DAPSA) scores, and Health Assessment Questionnaire scores (P < 0.001). Patients with axPsA who had dactylitis, as compared to those who did not, also had higher values for the Disease Activity Score in 28 joints, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Functional Index, and Bath Ankylosing Spondylitis Disease Activity Index (P < 0.05), while fewer of these patients met the criteria for minimal disease activity and low disease activity (P < 0.05). Consistently, they had more severe damage as detected by radiography (P < 0.05), higher sacroiliac scores (odds ratio [OR] 2.08, 95% CI 1.14-3.79; P = 0.02), and a more significant reduction in bone mass density (OR 2.42, 95% CI 1.34-4.37; P = 0.003). No statistical differences were observed regarding HLA-B27 and the Leeds Enthesitis Index between these 2 groups of patients. Notably, only half of the patients with dactylitic axPsA had inflammatory back pain. CONCLUSION: Our study demonstrated that patients with axPsA who had dactylitis had higher disease activity and more severe joint damage compared to those without dactylitis. Careful examination and proper management of axial involvement are recommended.

QRISK3-based analysis of cardiovascular risk factors in patients with long-term but well-controlled systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease of unknown etiology. Corticosteroids and immunosuppressive agents are the principal forms of treatment for this condition. While cardiovascular disease (CVD) is known to be a major cause of death in patients with SLE, there has been no improvement over the last few decades with regard to diagnosis, treatment, or prognosis. The QRISK3 algorithm is a new algorithm that includes SLE-related risk factors; this tool can predict the risk of CVD over a ten-year period. In this study, involving 180 patients, we compared the performance of the Framingham risk score, the recalibrated risk prediction SCORE, and QRISK3 for the assessment of CVD in patients with a long course of disease and low disease activity. Then, we used a more efficient algorithm, QRISK3 to identify the risk factors for CVD. This was a prospective and cross-sectional study involving 116 patients. All patients fulfilled the ACR criteria. The systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) is widely used to assess disease activity in SLE patients; patients with a SLEDAI-2K less than or equal to 4 are considered to be stable. Thus, we defined well-controlled patients as those with a SLEDAI-2K score less than or equal to 4. The dose of glucocorticoid (GC) that patients received was less or equal to 10 mg per day. We recorded and assessed a range of traditional risk factors, current treatments, comorbidities, data at the time of onset, and SLE-related evaluations. The QRISK3 score, and the relative risk (RR) that this score defined, were used to estimate the risk of CVD in patients with SLE. According to these relative risks, the patients were divided into low- (n=28), intermediate- (n=46), and high-relative risk (n=31) groups for subgroup analysis. Of the 116 patients enrolled, 105 were eligible to be assessed for the risk of CVD. By univariate analyses, the RR was significantly related with age at the time of enrolment (p<0.001), age at onset (p<0.001), resting heart rate (RHR) (p<0.001), present dose of GCs (p<0.001), present SLEDAI-2K (p=0.015), aerobic exercise (p<0.001), initial SLEDAI-2K (p<0.001), and initial dose of GCs (p=0.048). In the multiple linear regression model, the RR of CVD was significantly correlated with the initial SLEDAI-2K score (ß=2.112, p<0.001), initial dose of GCs (ß=-0.009, p=0.041), resting heart rate (ß=0.241, p=0.003) and age at onset (ß=-0.208, p=0.004). Pearson's correlation showed that RHR was significantly associated with aerobic exercise (r=-0.322, p=0.001). Subgroup analysis further identified a positive correlation between the history of nephritis, metabolic syndrome (MetS), aerobic exercise, present dose of GCs, and the RR of CVD. Patients with long-term but well-controlled SLE had a high relative risk of CVD and that this was associated with resting heart rate (P=0.003), history of lupus nephritis (P<0.001), initial SLEDAI-2K score (P<0.001), and metabolic syndrome (P=0.017). However, age at onset (P<0.001), use of hydroxychloroquine (P=0.30) and Mycophenolate mofetil (P=0.01), and the initial dose of glucocorticoid (P=0.049), were protective factors. Younger SLE patients had a significantly higher relative risk of CVD than older patients (p<0.001). QRISK3 detected more SLE patients at high risk of CVD when compared to the Framingham and recalibrate SCORE. To reduce the risk of CVD in SLE patients, measures should be taken both during the initial stages of disease and for long-term management.

Characterisation of Disease Patterns of Dermatomyositis with Different Initial Manifestations.

Purpose: To determine the characteristics and prognoses of dermatomyositis (DM) by comparing the difference in initial symptoms. Patients and Methods: A retrospective analysis was performed on the patients diagnosed with DM from 1 January 2019 to 1 January 2021. Based on the firstly presented symptoms, patients were divided into five groups, namely rash group, muscle weakness group, arthritis group, respiratory symptom group and atypical symptom group. Clinical and laboratory data were recorded. All patients were followed up until 31 May 2021. Results: In total 136 DM patients, rash (40%) was the most common initial symptom, followed by respiratory symptoms (22%), arthritis (20%), muscle weakness (10%) and atypical symptoms (8%). Rash group and atypical group had a higher positive rate of anti-TIF1γ antibodies than arthritis group and respiratory symptom group (P < 0.05). Respiratory symptom and arthritis groups had a higher positive rate of anti-Ro52 antibodies than rash and muscle weakness groups (P < 0.05). Respiratory group had a higher incidence of ILD than rash and atypical groups. The FVC and DLCO in respiratory group were significantly lower than rash group, arthritis group and atypical group (P < 0.05). The survival rate of rash group was significantly higher than muscle weakness group and arthritis group (P < 0.05). Conclusion: DM patients with different initial manifestations had different myositis antibodies and prognoses.

Bone Marrow Mesenchymal Stem Cells Overexpressing HIF-1α Prevented the Progression of Glucocorticoid-Induced Avascular Osteonecrosis of Femoral Heads in Mice.

Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)-PGE-2 (prostaglandin E2)-HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2-/-) mice were subjected to micro-computed tomography and histological examinations. Compared with their WT littermates, COX-2-/- mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.

Risk factors for progression of interstitial lung disease in Sjögren's syndrome: a single-centered, retrospective study.

OBJECTIVE: To identify clinical characteristics and risk factors related to the progression of interstitial lung disease (ILD) in patients with primary Sjögren's syndrome (pSS). METHODS: In this single-centered, retrospective study, a total of 83 identified pSS-ILD patients with relatively complete clinical data were finally enrolled. Clinical symptoms, laboratory data, high-resolution computed tomography (HRCT), and pulmonary function test (PFT) results were collected. A logistic regression analysis was performed to determine the independent risk factors for ILD progression, and a nomogram was plotted to construct a predictive model. RESULTS: The prevalence of pSS-ILD in our study was 18.89%. Among the 83 enrolled patients, 32 (38.6%) underwent ILD progression. The characteristic features associated with the progression of ILD included male sex, non-sicca onset, reticular pattern on HRCT, higher levels of baseline lactic dehydrogenase (LDH), and low baseline forced vital capacity (FVC). The results of multivariate logistic regression indicated that LDH (OR 1.008, p = 0.030) was an independent risk factor for ILD progression, while sicca onset (OR 0.254, p = 0.044) and FVC (OR 0.952, p = 0.003) were protective factors for ILD progression. A simple predictive model for ILD progression in pSS was developed and validated. CONCLUSION: pSS patients with non-sicca onset, high baseline LDH level, and low baseline FVC were at higher risk of ILD progression.

Smad3 prevents beta-catenin degradation and facilitates beta-catenin nuclear translocation in chondrocytes.

Our previous study demonstrated that transforming growth factor (TGF)-beta activates beta-catenin signaling through Smad3 interaction with beta-catenin in chondrocytes. In the present studies, we further investigated the detailed molecular mechanism of the cross-talk between TGF-beta/Smad3 and Wnt/beta-catenin signaling pathways. We found that C-terminal Smad3 interacted with both the N-terminal region and the middle region of beta-catenin protein in a TGF-beta-dependent manner. Both Smad3 and Smad4 were required for the interaction with beta-catenin and protected beta-catenin from an ubiquitin-proteasome-dependent degradation. In addition, the formation of the Smad3-Smad4-beta-catenin protein complex also mediated beta-catenin nuclear translocation. This Smad3-mediated regulatory mechanism of beta-catenin protein stability enhanced the activity of beta-catenin to activate downstream target genes during chondrogenesis. Our findings demonstrate a novel mechanism between TGF-beta and Wnt/beta-catenin signaling pathways during chondrocyte development.