Berberine: A Traditional Natural Product With Novel Biological Activities.

CONTEXT: Having been used for thousands of years to treat gastrointestinal diseases, the natural isoquinoline alkaloid, berberine, has exhibited a wide spectrum of biochemical and pharmacological effects in studies of recent years. OBJECTIVE: The review intended to examine the many novel bioactivities of berberine, including antidiabetic, anticancer, neuroprotective, anti-inflammatory, and anti-atherosclerotic actions. DESIGN: The research team searched the MEDLINE database using PubMed, using different keyword combinations, including berberine AND diabetes, berberine AND cancer, berberine AND (neuron OR brain), berberine AND inflammation, and "berberine AND atherosclerosis to find studies evaluating the various effects exerted berberine. CONCLUSION: Berberine is a promising multipotent agent to combat diabetes, cancer, Alzheimer's disease, and other diseases.

Geographical heterogeneity and inequality of access to improved drinking water supply and sanitation in Nepal.

BACKGROUND: Per United Nations' Sustainable Development Goals, Nepal is aspiring to achieve universal and equitable access to safe and affordable drinking water and provide access to adequate and equitable sanitation for all by 2030. For these goals to be accomplished, it is important to understand the country's geographical heterogeneity and inequality of access to its drinking-water supply and sanitation (WSS) so that resource allocation and disease control can be optimized. We aimed 1) to estimate spatial heterogeneity of access to improved WSS among the overall Nepalese population at a high resolution; 2) to explore inequality within and between relevant Nepalese administrative levels; and 3) to identify the specific administrative areas in greatest need of policy attention. METHODS: We extracted cluster-sample data on the use of the water supply and sanitation that included 10,826 surveyed households from the 2011 Nepal Demographic and Health Survey, then used a Gaussian kernel density estimation with adaptive bandwidths to estimate the distribution of access to improved WSS conditions over a grid at 1 × 1 km. The Gini coefficient was calculated for the measurement of inequality in the distribution of improved WSS; the Theil L measure and Theil T index were applied to account for the decomposition of inequality. RESULTS: 57% of Nepalese had access to improved sanitation (range: 18.1% in Mahottari to 100% in Kathmandu) and 92% to drinking-water (range: 41.7% in Doti to 100% in Bara). The most unequal districts in Gini coefficient among improved sanitation were Saptari, Sindhuli, Banke, Bajura and Achham (range: 0.276 to 0.316); and Sankhuwasabha, Arghakhanchi, Gulmi, Bhojpur, Kathmandu (range: 0.110 to 0.137) among improved drinking-water. Both the Theil L and Theil T showed that within-province inequality was substantially greater than between-province inequality; while within-district inequality was less than between-district inequality. The inequality of several districts was higher than what is calculated by regression of the Gini coefficient and our estimates. CONCLUSIONS: This study showed considerable geographical heterogeneity and inequality not evidenced in previous national statistics. Our findings may be useful in prioritizing resources to reduce inequality and expand the coverage of improved water supply and sanitation in Nepal.

[Chemical constituents from Impatiens pritzllii var. hupehensis].

Eight compounds were isolated from the 50% ethanol extract of Impatiens pritzllii var.hupehensis through various column chromatography methods including silica gel, Sephadex LH-20, and preparative HPLC. Their structures were elucidated as 2,6-dimethyl-2-vinyl-2,3,4,7-tetrahydrooxepine(1), 1,3,6-trihydroxy-7-methyl-anthraquinone(2),4-hydroxybenzaldehyde(3),4-(3-methoxy-4-hydroxyphenyl)-2-butanone(4), podophyllotoxin(5),scopoletin(6), α-spinasterol(7) and 3-O-ß-D-glucopyranosyl-α-spinasterol(8) based on the NMR and MS spectral data. Compound 1 is new compound and compounds 2-8 are isolated from this plant for the first time.

Chemical constituents from stems and leaves of Micromelum integerrimum.

A new benzene derivative microintegerrin C (1) and a new norsesquiterpenoid microintegerrin D (2), along with six known compounds (3-8), were isolated and identified from stems and leaves of Micromelum integerrimum by various chromatographies such as silica gel, Sephadex LH-20, RP-18 column chromatography and HPLC. Their structures were mainly identified based on the spectral data analysis such as 1D-, 2D-NMR and HR-EI-MS. All known compounds were isolated from this plant for the first time.

Report: Cytotoxic flavonoids from the young twigs and leaves of Caesalpinia bonduc (Linn) Roxb.

The extraction, fractionation and recognition of flavonoids from the ethanolic extract of young twigs and leaves of C. bonduc were carried out. In addition, cytotoxic study of the flavonoids on two cancer cell lines, BGC-823 and HeLa was carried our using sulphorhodamine B assay. Seven flavonoids, six of which are being reported for the first time in this plant, were isolated. Their structures were identified by MS and NMR spectroscopic methods. Petroleum ether, ethyl acetate and water fractions exhibited moderate cytotoxic activity against HeLa cells. Five compounds showed cytotoxic activity against HeLa cell in comparison with Paclitaxel, while only one compound showed a good degree of cytotoxic activity against BGC-823 cell in comparison to Paclitaxel. The results obtained showed a structure - activity relationship.

New dicyclopeptides from Dianthus chinensis.

One new dicyclopeptide cyclo-(L-N-methyl Glu-L-N-methyl Glu) (1), together with one new natural dicyclopeptide cyclo-(L-methyl Glu ester-L-methyl Glu ester) (2), and two known dicyclopeptides cyclo-(L-methyl Glu ester-L-Glu) (3), and cyclo-(L-Glu-L-Glu) (4), were isolated from the aerial parts of Dianthus chinensis L. Their structures were determined by spectroscopic analyses and chemical methods.

Astataricusones A-D and astataricusol A, five new anti-HBV shionane-type triterpenes from Aster tataricus L. f.

Five new shionane-type triterpenes, astataricusones A-D (compounds 1-4) and astataricusol A (5), together with one known shionane-type triterpene 6 were obtained from the roots and rhizomes of Aster tataricus L. f. Their structures were elucidated on the basis of spectroscopic data, mainly NMR and MS data. The absolute configurations of 1 and 4 was determined by single crystal X-ray diffraction and CD analysis. Compound 2 showed inhibitory activity on HBsAg secretion with an IC50 value of 23.5 µM, while 2 and 6 showed inhibitory activities on HBeAg secretion with IC50 values of 18.6 and 40.5 µM, and cytotoxicity on HepG 2.2.15 cells with CC50 values of 172.4 and 137.7 µM, respectively. Compounds 2 and 6 also exhibited inhibitory activities on HBV DNA replication with IC50 values of 2.7 and 30.7 µM, respectively.

Transplantation of human induced pluripotent stem cell derived keratinocytes accelerates deep second-degree burn wound healing.

BACKGROUND: Current evidence shows that human induced pluripotent stem cells (hiPSCs) can effectively differentiate into keratinocytes (KCs), but its effect on skin burn healing has not been reported. AIM: To observe the effects of hiPSCs-derived KCs transplantation on skin burn healing in mice and to preliminarily reveal the underlying mechanisms. METHODS: An analysis of differentially expressed genes in burn wounds based on GEO datasets GSE140926, and GSE27186 was established. A differentiation medium containing retinoic acid and bone morphogenetic protein 4 was applied to induce hiPSCs to differentiate into KCs. The expression of KCs marker proteins was detected using immunofluorescence staining. A model of a C57BL/6 mouse with deep cutaneous second-degree burn was created, and then phosphate buffered saline (PBS), hiPSCs-KCs, or hiPSCs-KCs with knockdown of COL7A1 were injected around the wound surface. The wound healing, re-epithelialization, engraftment of hiPSCs-KCs into wounds, proinflammatory factor level, and the NF-κB pathway proteins were assessed by hematoxylin-eosin staining, carboxifluorescein diacetate succinimidyl ester (CFSE) fluorescence staining, enzyme linked immunosorbent assay, and Western blotting on days 3, 7, and 14 after the injection, respectively. Moreover, the effects of COL7A1 knockdown on the proliferation and migration of hiPSCs-KCs were confirmed by immunohistochemistry, EdU, Transwell, and damage repair assays. RESULTS: HiPSCs-KCs could express the hallmark proteins of KCs. COL7A1 was down-regulated in burn wound tissues and highly expressed in hiPSCs-KCs. Transplantation of hiPSCs-KCs into mice with burn wounds resulted in a significant decrease in wound area, an increase in wound re-epithelialization, a decrease in proinflammatory factors content, and an inhibition of NF-κB pathway activation compared to the PBS group. The in vitro assay showed that COL7A1 knockdown could rescue the inhibition of hiPSCs-KCs proliferation and migration, providing further evidence that COL7A1 speeds up burn wound healing by limiting cell proliferation and migration. CONCLUSION: In deep, second-degree burn wounds, COL7A1 can promote KC proliferation and migration while also suppressing the inflammatory response.

Zizimauritic acids A-C, three novel nortriterpenes from Ziziphus mauritiana.

Zizimauritic acids A-C (1-3), three novel nortriterpenes with a unique A-nor-E-seco spiro-lactone ceanothane-type triterpene skeleton, together with 3 known triterpenes ceanothenic acid (4), betulinic acid (5), and ceanothic acid (6), were isolated from the roots of Ziziphus mauritiana. Compounds 1-4 showed cytotoxicities with the IC(50) values ranging from 5.05 to 11.94 µg/ml, and compounds 1 and 3 showed an inhibitory effect on the growth of Staphylococcus aureus with the IC(50) values 2.17 and 12.79 µg/ml. A plausible biosynthetic pathway of compounds 1-3 was proposed.

[Progress in the study of some important natural bioactive cyclopeptides].

Natural cyclopeptides are hot spots in chemical and pharmaceutical fields because of the wide spreading bio-resources, complex molecular structures and various bioactivities. Bio-producers of cyclopeptides distribute over almost every kingdom from bacteria to plants and animals. Many cyclopeptides contain non-coded amino acids and non-pepditic bonds. Most exciting characteristic of cyclopeptides is a range of interesting bioactivities such as antibiotics gramicidin-S (2), vancomycin (3) and daptomycin (4), immunosuppressive cyclosporin-A (1) and astin-C (8), and anti-tumor aplidine (5), RA-V (6) and RA-VII (7). Compounds 1-4 are being used in clinics; compounds 5-8 are in the stages of clinical trial or as a candidate for drug research. In this review, the progress in chemical and bioactive studies on these important natural bioactive cyclopeptides 1-8 are introduced, mainly including discovery, bioactivity, mechanism, QSAR and synthesis.

[Soil organic carbon density and its influencing factors in croplands with different cultivation years in the Northeastern Ulan Buh Desert, China]. / ä¹Œå °å¸ƒå’Œæ²™æ¼ ä¸œåŒ—éƒ¨ä¸åŒè€•ä½œå¹´é™å†œç”°åœŸå£¤æœ‰æœºç¢³å¯†åº¦åŠå ¶å½±å“å› ç´ .

Understanding the changes and influencing factors of soil organic carbon density (SOCD) during the conversion of uncultivated natural soil to croplands is of great significance for the assessment of carbon sequestration in arid areas. In this study, we compared SOCD in the uncultivated soil and that in croplands with different cultivation years (2-5, 12-15, 25-30, 40-50 years) in the Northeastern Ulan Buh Desert. The change of SOCD and its influencing factors at 0-2 m soil depth during the conversion of uncultivated natural soil to croplands were explored by the method of replacing time with space. The results showed that SOCD at the shallow soil depth (0-0.4 m) in croplands increased continuously with cultivation years, but basically at low levels (0.990-1.983 kg·m-2). The SOCD at deep soil (1.2-2 m) increased in the croplands with longer cultivation years (25-30 and 40-50 years), whereas no obvious change trends in both the croplands with shorter cultivation years (2-5 and 12-15 years) and the uncultivated natural soil. The SOCD at deep soil (1.2-2 m) were relatively large (28.9%-38.6%) of the 0-2 m soil depth of uncultivated natural soil and croplands with different cultivation years. The vertical distribution of SOCD in croplands with different cultivation years were well fitted by quadratic functions (with R2 ranging from 0.757 to 0.972). It was noteworthy that soil clay and silt contents had dominant influences on SOCD at all the soil profile (0-2 m), and that cultivation years mainly contributed to the accumulation of SOC at the shallow soil (0-0.4 m).

Cyclopeptide Alkaloids from Ziziphus apetala.

Six novel Ia3-type cyclopeptide alkaloids (1-6) were isolated from stems of Ziziphus apetala. Compound 5 and the known compounds mauritine A (7) and mauritine F (8) were isolated from the roots. Their structures were determined by spectroscopic analyses and chemical methods. The total alkaloids from the roots and the isolated cyclopeptide alkaloids were tested for antidepressant behavior on mice, cytotoxicity, and 11ß-hydroxysteroid dehydrogenase (11ß-HSD) inhibition in vitro. Only mauritine A (7) showed inhibitory activity on 11ß-HSD1, with IC50 values of 52.0 (human) and 31.2 µg/mL (mouse).

Antimicrobial, cytotoxic lignans and terpenoids from the twigs of Pseudolarix kaempferi.

Seven new compounds, including four lignans, (+)-(8S,8'S)-9,9'-dibenzoylsecoisolariciresinol (1), (+)-(8S*,8'R*)-4,4'-dimethyloxomatairesinol (2), (+)-(7S*,8R*,8'R*,9'S*)-9'-n-butoxytsugacetal (3), and pseudolarkaemin A (4), a pyronane glycoside, pseudolarkaemin B (5), an ent-beyerene glycoside, pseudolarkaemin C (6), and a triterpene, 25-epi-pseudolarolide Q (7), along with 25 known compounds (8­32) were isolated from the twigs of Pseudolarix kaempferi. Their structures were elucidated mainly by the analysis of their NMR and MS data. Pseudolarolide C acid (24) was isolated for the first time as a natural product. All compounds were evaluated for antimicrobial activity against Candida albicans and Staphylococcus aureus, and cytotoxic activity against K562, HT-29, B16, BGC-823, BEL-7402, SGC-7901, U251, and A549 cancer cell lines were assayed. Results indicated that the new compounds 3, 7, and some known compounds showed antimicrobial and cytotoxic activities.

A gene-expression-based signature predicts survival in adults with T-cell lymphoblastic lymphoma: a multicenter study.

We aimed to establish a discriminative gene-expression-based classifier to predict survival outcomes of T-cell lymphoblastic lymphoma (T-LBL) patients. After exploring global gene-expression profiles of progressive (n = 22) vs. progression-free (n = 28) T-LBL patients, 43 differentially expressed mRNAs were identified. Then an eleven-gene-based classifier was established using LASSO Cox regression based on NanoString quantification. In the training cohort (n = 169), high-risk patients stratified using the classifier had significantly lower progression-free survival (PFS: hazards ratio 4.123, 95% CI 2.565-6.628; p < 0.001), disease-free survival (DFS: HR 3.148, 95% CI 1.857-5.339; p < 0.001), and overall survival (OS: HR 3.790, 95% CI 2.237-6.423; p < 0.001) compared with low-risk patients. The prognostic accuracy of the classifier was validated in the internal testing (n = 84) and independent validation cohorts (n = 360). A prognostic nomogram consisting of five independent variables including the classifier, lactate dehydrogenase levels, ECOG-PS, central nervous system involvement, and NOTCH1/FBXW7 status showed significantly greater prognostic accuracy than each single variable alone. The addition of a five-miRNA-based signature further enhanced the accuracy of this nomogram. Furthermore, patients with a nomogram score ≥154.2 significantly benefited from the BFM protocol. In conclusion, our nomogram comprising the 11-gene-based classifier may make contributions to individual prognosis prediction and treatment decision-making.

A CpG Methylation Classifier to Predict Relapse in Adults with T-Cell Lymphoblastic Lymphoma.

PURPOSE: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. EXPERIMENTAL DESIGN: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort (n = 160). The four-CpG classifier was validated in the internal testing cohort (n = 68) and independent validation cohort (n = 321). RESULTS: The four-CpG-based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk (P < 0.001). This classifier also showed good predictive value in the internal testing cohort (P < 0.001) and the independent validation cohort (P < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and NOTCH1/FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation. CONCLUSIONS: Our four-CpG-based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision.

Echinacoside elicits endothelium-dependent relaxation in rat aortic rings via an NO-cGMP pathway.

The aim of this study was to identify and elucidate the vasorelaxant activity of echinacoside, a phenylethanoid glycoside isolated from the medicinal herb Cistanche tubulosa, and its possible underlying mechanism on isolated rat thoracic aortic rings pre-contracted with phenylephrine (PE, 1 microM) and KCl (60 mM). Echinacoside (30-300 microM) exhibited an acute relaxation in endothelium-intact rings in a concentration-dependent manner, while this relaxation was significantly inhibited in endothelium-denuded condition and in the presence of the endothelial nitric oxide synthase (eNOS) inhibitor, N(W)-nitro-L-arginine methyl ester (L-NNA, 100 microM), an unselective soluble guanylate cyclase blocker, methylene blue (10 microM), the selective sGC inhibitor 1 H-[1, 2, 4]oxadiazolo[4,3- A]quinoxalin-1-one (ODQ, 1 microM); in addition, atropine (1 microM), a selective muscarinic receptor antagonist, partially affected the relaxation. However, the cyclooxygenase inhibitor indomethacin (5 microM) had no influence on the action. Echinacoside enhanced the cyclic guanosine monophosphate (cGMP) production in aortic rings contracted with PE. These results indicate for the first time that echinacoside mediates the endothelium-dependent vasodilator action in rat thoracic aortic rings through nitric oxide (NO)-cGMP pathway.

[Hydrochemical Characteristics of Karst Groundwater in the Mountains of Northern Bazhong City, China].

To study the hydrogeochemical characteristics and formation mechanism of groundwater in a karst development transition zone in southern and northern China, 25 groundwater samples were collected from the Shuangfengya area in the northern part of Bazhong City. Descriptive statistics, coefficients of variation, Schoeller diagrams, Sukalev classification, Piper diagrams, and Gibbs and ion scale coefficients were used to analyze the karst water chemistry and distribution characteristics. The main processes controlling the chemical evolution of the groundwater are also discussed. The research shows that the degree of groundwater mineralization in the study area is generally low, with mostly neutral water and alkaline water. There are some differences in groundwater between the northern and southern regions; the anions and cations in the groundwater in the northern area were mainly HCO3-, Ca2+, and Mg2+, with HCO3-Ca·Mg being the main water chemistry type; the anions and cations in the groundwater in the northern area were mainly HCO3-, and Ca2+, and HCO3-Ca was the main water chemistry type. The chemical character of groundwater was controlled by rock weathering and alternate cation adsorption, and evaporation crystallization in the southern region was more significant than in the northern region. Furthermore, rainfall in the northern region had a more significant effect on groundwater geochemistry than in the south. The differences in climate and lithology between the northern and southern region are the dominant factors influencing the differences in hydrochemistry.

Evolution and Dosimetric Analysis of Magnetic Resonance Imaging-Detected Brain Stem Injury After Intensity Modulated Radiation Therapy in Nasopharyngeal Carcinoma.

PURPOSE: To evaluate the evolution of radiation-induced brain stem injury (BSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT) and to identify the critical dosimetric predictors of BSI. METHODS AND MATERIALS: A total of 6288 NPC patients treated with IMRT between 2009 and 2015 were retrospectively reviewed. Among these 6288 patients, 24 had radiation-induced BSI, which manifested as edematous lesions and contrast-enhanced lesions (CLs) on magnetic resonance imaging. Latency, symptoms, and evolution of BSI were assessed. Critical dosimetric predictors of BSI were identified using a penalized regression model with performance evaluated by receiver operating characteristic curve analysis. RESULTS: Median BSI latency was 14.5 months (range, 7.6-37.5 months), and 9 out of 24 patients (37.5%) were clinically symptomatic. Edematous lesions and CLs were both present in all patients. Necrosis was significantly more common in larger CLs (P = .007). After median follow-up of 12.5 months, 13 out of 24 patients (54.2%) had complete remission, and 5 out of 24 patients (20.8%) had partial remission. Remission was unaffected by whether or not symptomatic treatment was given. Maximum point dose (Dmax) was identified as the critical predictor of BSI (area under the receiver operating curve = 0.898), with the optimal cutoff equivalent dose in 2-Gy fractions (D2) being 67.4 Gy (sensitivity = 0.833, 20 out of 24; specificity = 0.835, 5234 out of 6264). Patients with Dmax ≥67.4 Gy (D2) were significantly more likely to develop BSI (odds ratio = 25.29; 95% CI, 8.63-74.14; P < .001) than those with Dmax <67.4 Gy (D2). CONCLUSIONS: In patients with NPC treated with IMRT, BSI generally tends to improve over time. Dmax = 67.4 Gy (D2) appears to be the dose constraint for brain stem, potentially providing clinicians with greater choice and flexibility when balancing the tumor target coverage and brain stem protection. Further studies are needed to validate our findings.

Prognostic and predictive value of a microRNA signature in adults with T-cell lymphoblastic lymphoma.

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.

Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor.

OBJECTIVE: It has been reported that ADAMTS-12 is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS-12 is reported to be required for inflammation in otherwise healthy subjects. This study was undertaken to determine the role of ADAMTS-12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis. METHODS: The collagen-induced arthritis (CIA) model was established in ADAMTS-12-deficient mice and their control littermates to determine the role of ADAMTS-12 in vivo. Micro-computed tomography scanning was used to demonstrate the destruction of the ankle joint; histologic analysis illustrated synovitis, pannus formation, and bone and cartilage destruction; enzyme-linked immunosorbent assay was performed to measure serum levels of inflammatory cytokines; and protein-protein interaction assays were performed to detect the interactions of ADAMTS-12 and its various deletion mutants with connective tissue growth factor (CTGF). RESULTS: Deficiency of ADAMTS-12 led to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS-12 caused enhanced osteoclastogenesis. In vitro and in vivo protein-protein interaction assays demonstrated that ADAMTS-12 bound and processed CTGF, a previously unrecognized substrate of ADAMTS-12. In addition, deletion of ADAMTS-12 enhanced, while overexpression of ADMATS-12 reduced, CTGF-mediated inflammation. Furthermore, ADAMTS-12 regulation of inflammation was largely lost in CTGF-deficient macrophages. Importantly, blocking of CTGF attenuated elevated inflammatory arthritis seen in the ADAMTS-12-deficient CIA mouse model. CONCLUSION: This study provides evidence that ADAMTS-12 is a critical regulator of inflammatory arthritis and that this is mediated, at least in part, through control of CTGF turnover.