Dataset Information

Synergistic Effects of Erzhi Pill Combined With Methotrexate on Osteoblasts Mediated via the Wnt1/LRP5/?-Catenin Signaling Pathway in Collagen-Induced Arthritis Rats.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by chronic synovitis, bone erosion, and bone loss. Erzhi Pill (EZP), a classic Chinese patent medicine, is often used to treat osteoporosis and shows a capacity for bone metabolism regulation. Methotrexate (MTX), an essential drug for RA treatment, has been reported to inhibit generalized bone loss in RA patients. However, the combined therapeutic effects and mechanism of EZP and MTX in RA have not been fully elucidated. The aim of this study was to investigate the synergistic effect of EZP and MTX on RA and to explore the underlying mechanism through network pharmacological prediction and experimental verification. Chemical compounds of EZP, human target proteins of EZP and MTX, and RA-related human genes were identified in the Encyclopedia of Traditional Chinese Medicine database, PubChem database, and NCBI database, respectively. The molecular network of EZP and MTX in RA was generated and analyzed with Ingenuity Pathway Analysis software according to the datasets. Then, MTX monotherapy, EZP monotherapy, and combined MTX and EZP therapy were administered to collagen-induced arthritis rats, followed by assessment of pathological score, bone damage, bone alkaline phosphatases (BALP), and tartrate-resistant acid phosphatase (TRACP), and of gene levels related to the Wnt1/LRP5/?-catenin pathway according to network pharmacological analysis. Finally, serum samples from MTX-, EZP- and MTX+EZP-treated rats were used to treat the rat osteoblast (OB)-like UMR-106 cell line to evaluate gene levels related to Wnt1/LRP5/?-catenin. Network pharmacological analysis showed that the Wnt/?-catenin signaling pathway was the top signaling pathway shared among MTX, EZP, and RA. The results from in vivo experiments indicated that EZP combined with MTX reduced arthritis severity, alleviated ankle bone damage, increased BALP and decreased TRACP serum levels, and regulated the mRNA expression of Wnt1, LRP5, ?-catenin, Runx2, BALP, and BGP in the ankles. In vitro experiments showed that EZP combined with MTX could also improve the expression of genes related to the Wnt1/LRP5/?-catenin pathway. This study demonstrated that EZP in combination with MTX played a synergistic role in regulating OBs in RA, which was connected to the modulatory effect of EZP and MTX on the Wnt1/LRP5/?-catenin signaling pathway.

SUBMITTER: Li X

PROVIDER: S-EPMC7079734 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synergistic Effects of Erzhi Pill Combined With Methotrexate on Osteoblasts Mediated <i>via</i> the Wnt1/LRP5/<i>β</i>-Catenin Signaling Pathway in Collagen-Induced Arthritis Rats.

Li Xiaoya X Lu Xiangcheng X Fan Danping D Li Li L Lu Cheng C Tan Yong Y Xia Ya Y Zhao Hongyan H Fan Miaoxuan M Xiao Cheng C

Frontiers in pharmacology 20200311

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by chronic synovitis, bone erosion, and bone loss. Erzhi Pill (EZP), a classic Chinese patent medicine, is often used to treat osteoporosis and shows a capacity for bone metabolism regulation. Methotrexate (MTX), an essential drug for RA treatment, has been reported to inhibit generalized bone loss in RA patients. However, the combined therapeutic effects and mechanism of EZP and MTX in RA have not been fully elucid ...[more]

PMID: 32218732

Similar Datasets

Project description:Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of ?-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of ?-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require ?-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of ?-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate ?-catenin signaling in osteoblasts. Consistent with a lack of ?-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of ?-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate ?-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

Project description:BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by swelling and painful joints, eventually leading to joint destruction. There is still a lack of effective therapy to treat RA. The Juanbi pill is a Chinese medicine that has been widely used to treat active RA in China for hundreds of years, relieving pain and protecting the affected joints from malformation. However, there is no solid evidence to show the effect of the Juanbi pill on the management of active RA.Methods/designWe will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial to determine whether the traditional Chinese medicine Juanbi pill could relieve joint pain in RA and protect the joints. A total of 120 patients with active RA will be enrolled and treated with the Juanbi pill or a placebo for 3 months. The primary outcome measures are as follows: rate of in the American College of Rheumatology (ACR)50, change in the 28-joint Disease Activity Score (DAS28) from baseline at beginning of therapy to 3 months, and a change in the van der Heijde modified Sharp score measured from baseline to 12 months. The secondary outcome measures are as follows: rate of change in ACR20, ACR70, Health Assessment Questionnaire-Disability Index (HAQ-DI), and change in score in the Patient Assessment of Arthritis Pain, Patient Global Assessment of Arthritis, and the Athens Insomnia Scale (AIS) from baseline to 2-week, 1-month, 2-month, 3-month, 6-month, and 12-month follow up. In addition, the rate of change (score) in the ACR50 and DAS28 from the baseline to 2-week, 1-month, 2-month, 6-month, and 12-month follow up are also the secondary outcome measures.DiscussionAlthough the Juanbi pill has been used in China for many years to treat RA, there is a lack of consensus about its effectiveness. This trial will provide convincing evidence about the effect of Juanbi pill on active RA.Trial registrationClinicalTrials.gov, NCT02885597 . Registered on 30 August 2016.

Dataset Information

Synergistic Effects of Erzhi Pill Combined With Methotrexate on Osteoblasts Mediated via the Wnt1/LRP5/?-Catenin Signaling Pathway in Collagen-Induced Arthritis Rats.

Publications

Synergistic Effects of Erzhi Pill Combined With Methotrexate on Osteoblasts Mediated <i>via</i> the Wnt1/LRP5/<i>β</i>-Catenin Signaling Pathway in Collagen-Induced Arthritis Rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets