Erosive Arthritis and Hepatic Granuloma Formation Induced by Peptidoglycan Polysaccharide in Rats Is Aggravated by Prasugrel Treatment

Authors

Analia E. Garcia, Mario C. Rico, Elisabetta Liverani, Raul A. DeLa Cadena, Paul F. Bray, Satya P. Kunapuli

Abstract

Administration of the thienopyridine P2Y12 receptor antagonist, clopidogrel, increased the erosive arthritis induced by peptidoglycan polysaccharide (PG-PS) in rats or by injection of the arthritogenic K/BxN serum in mice. To determine if the detrimental effects are caused exclusively by clopidogrel, we evaluated prasugrel, a third-generation thienopyridine pro-drug, that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine. Prasugrel effects were examined on the PG-PS-induced arthritis rat model. Erosive arthritis was induced in Lewis rats followed by treatment with prasugrel for 21 days. Prasugrel treated arthritic animals showed a significant increase in the inflammatory response, compared with untreated arthritic rats, in terms of augmented macroscopic joint diameter associated with significant signs of inflammation, histomorphometric measurements of the hind joints and elevated platelet number. Moreover, fibrosis at the pannus, assessed by immunofluorescence of connective tissue growth factor, was increased in arthritic rats treated with prasugrel. In addition to the arthritic manifestations, hepatomegaly, liver granulomas and giant cell formation were observed after PG-PS induction and even more after prasugrel exposure. Cytokine plasma levels of IL-1 beta, IL-6, MIP1 alpha, MCP1, IL-17 and RANTES were increased in arthritis-induced animals. IL-10 plasma levels were significantly decreased in animals treated with prasugrel. Overall, prasugrel enhances inflammation in joints and liver of this animal model. Since prasugrel metabolites inhibit neutrophil function ex-vivo and the effects of both clopidogrel and prasugrel metabolites on platelets are identical, we conclude that the thienopyridines metabolites might exert non-platelet effects on other immune cells to aggravate inflammation.

Link to Article

http://dx.doi.org/10.1371/journal.pone.0069093

From Meniscus to Bone: Structure and Function of Human Meniscal Entheses and Deleterious Effects of Osteoarthritis

Author

Adam Christopher Abraham

Abstract

Knee osteoarthritis plagues millions of people in the U.S. alone, yet the mechanisms of initialization are not well understood. Recent work suggests that there are a myriad of potential disease inducing routes that may give rise to this debilitating condition. Understanding and elucidating the potential pathways leading to osteoarthritis may result in novel methods of prevention and/or treatment. Human meniscus areC-shaped fibrocartilaginous structures contained within the diathroidal knee joint, the primary function of which are to provide support and lubrication between the femur and the tibia. Each knee incorporates two menisci, lateral and medial, affixed at the anterior and posterior attachment sites to the tibial plateau. Meniscal attachments, or entheses, are unique graded tissue interfaces comprised of four distinct zones that diffuse longitudinal loads transmitted via hoop stresses of collagen fibrils in the meniscal body. The attachments must remain firmly rooted to the tibial plateau to effectively attenuate joint loads. If the attachments become structurally compromised, either through direct or indirect means, excessive transverse meniscal translation results. Such joint extrusion of the meniscal body is a known precursor to developing osteoarthritis. To date there have been no investigations of integrity of meniscal attachments in the aged arthritic knee.

Link to Article

http://digitool.library.colostate.edu/exlibris/dtl/d3_1/apache_media/L2V4bGlicmlzL2R0bC9kM18xL2FwYWNoZV9tZWRpYS8yMDc0NjQ=.pdf

Strontium ranelate reduces cartilage degeneration and subchondral bone remodeling in rat osteoarthritis model

Authors

De-gang Yu, Hui-feng Ding, Yuan-qing Mao, Ming Liu, Bo Yu, Xin Zhao,Xiao-qing Wang, Yang Li, Guang-wang Liu, Shao-bo Nie, Shen Liu andZhen-an Zhu

Abstract

Medial meniscal tear (MMT) operation was performed in adult SD rats to induce OA. SR (625 or 1800 mg·kg−1·d−1) was administered via gavage for 3 or 6 weeks. After the animals were sacrificed, articular cartilage degeneration was evaluated using toluidine blue O staining, SOX9 immunohistochemistry and TUNEL assay. The changes in microarchitecture indices and tissue mineral density (TMD), chemical composition (mineral-to-collagen ratio), and intrinsic mechanical properties of the subchondral bones were measured using micro-CT scanning, confocal Raman microspectroscopy and nanoindentation testing, respectively. The high-dose SR significantly attenuated cartilage matrix and chondrocyte loss at 6 weeks, and decreased chondrocyte apoptosis, improved the expression of SOX9, a critical transcription factor responsible for the expression of anabolic genes type II collagen and aggrecan, at both 3 and 6 weeks. Meanwhile, the high-dose SR also significantly attenuated the subchondral bone remodeling at both 3 and 6 weeks, as shown by the improved microarchitecture indices, TMD, mineral-to-collagen ratio and intrinsic mechanical properties. In contrast, the low-dose SR did not significantly change all the detection indices of cartilage and bone at both 3 and 6 weeks. The high-dose SR treatment can reduce articular cartilage degeneration and subchondral bone remodeling in the rat MMT model of OA.

Link to Article

http://dx.doi.org/10.1038/aps.2012.167

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function

Authors

Julia F. Charles, Lih-Yun Hsu, Erene C. Niemi, Arthur Weiss, Antonios O. Alipranti and Mary C. Nakamura

Abstract

Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b–/loLy6Chi BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell–suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint.

Link to Article

http://dx.doi.org/10.1172/JCI60920

In vivo bone-specific EphB4 overexpression in mice protects both subchondral bone and cartilage during osteoarthritis

Authors

Gladys Valverde-Franco PhD, Jean-Pierre Pelletier MD, Hassan Fahmi PhD, David Hum MSc, Koichi Matsuo MD, PhD, Bertrand Lussier DVM, MSc, Dipl. ACVS, Mohit Kapoor PhD, Johanne Martel-Pelletier PhD

Abstract

In vitro activation of the receptor EphB4 positively impacts human osteoarthritis (OA) articular cell metabolism. However, the specific in vivo role of this ephrin receptor in OA remains unknown. We investigated in mice the in vivo effect of bone-specific EphB4 overexpression on OA pathophysiology. Morphometric, morphological, and radiological evaluations were performed on postnatal day 5 (P5) and on 10-week-old mice. Knee OA was surgically induced (DMM) in 10-week-old male EphB4 homozygous (TgEphB4) and wild-type (WT) mice. Medial compartment evaluations of cartilage were performed using histology and immunohistochemistry, and of subchondral bone using histomorphometry, osteoclast staining, and micro-computed tomography. There was no obvious phenotypic difference in skeletal development between TgEphB4 and WT mice at P5 and 10 weeks. At 8 and 12 weeks post-DMM surgery, TgEphB4 mice demonstrated significantly less cartilage alteration than the WT in the medial tibial plateau and the femoral condyle. This was associated with a significant reduction in the operated TgEphB4 mice of aggrecan and type II collagen degradation products, type X collagen and collagen fibril disorganization. The medial tibial subchondral bone demonstrated at both times post-DMM surgery that, compared to the WT, the TgEphB4 mice had a significant reduction in sclerosis, bone volume, trabecular thickness, and number of tartrate resistant acid phosphatase positive osteoclasts.This is the first in vivo evidence that bone-specific EphB4 overexpression exerts a protective effect on OA joint structural changes. This study stresses the in vivo importance of subchondral bone biology in cartilage integrity.

Link to Article

http://dx.doi.org/10.1002/art.34638

Efficacy of zoledronic acid in treatment of osteoarthritis is dependent on the disease progression stage in rat medial meniscal tear model

Authors

De-gang Yu, Bo Yu, Yuan-qing Mao, Xin Zhao, Xiao-qing Wang, Hui-feng Ding, Lei Cao, Guang-wang Liu, Shao-bo Nie, Shen Liu and Zhen-an Zhu

Abstract

To investigate whether the stage of osteoarthritis (OA) progression influenced the efficacy of the third-generation bisphosphonate zoledronic acid in a rat medial meniscal tear model. Medial meniscal tear (MMT) was surgically induced in adult male Sprague Dawley rats. Zoledronic acid (ZOL, 100 μg/kg, sc, twice a week) was administered starting immediately, early (from 4 weeks) or late (from 8 weeks) after OA induction. The degeneration of articular cartilage was evaluated with toluidine blue O staining. Subchondral bone remodeling was evaluated with X-ray micro-CT scanning. Joint pain was measured with respect to weight-bearing asymmetry. Calcitonin gene-related peptide (CGRP) expression in dorsal root ganglia (DRGs) was examined using immunofluorescence analysis. The afferent neurons in DRGs innervating the joint were identified by retrograde labeling with fluorogold. Progressive cartilage loss was observed during 12 weeks after OA induction. Subchondral bone remodeling manifested as increased bone resorption at early stage (4 weeks), but as increased bone accretion at advanced stages (8 weeks). Immediately and early ZOL administration significantly improved subchondral microstructural parameters, attenuated cartilage degeneration, reduced weight-bearing asymmetry and CGRP expression, whereas the late ZOL administration had no significant effects. The stage of OA progression influences the efficacy of ZOL in treating joint degeneration and pain. To obtain the maximum efficacy, bisphosphonate treatment should be initiated in rat with early stages of OA pathogenesis.

Link to Article

http://dx.doi.org/10.1038/aps.2012.28