Article Text

PDF
SAT0318 Could Adrenomedullin be Considered as a Treatment for Osteoarthritis?
  1. A. Chatron-Colliet1,
  2. F. Velard1,
  3. D. Côme1,
  4. H. Lin1,
  5. H. K. Ea1,
  6. F. Lioté1
  1. 1Inserm U606, PARIS, France

Abstract

Background Osteoarthritis (OA) is a frequent articular disease which generally affects elderly people. Major hallmarks of OA are chondrolysis, chondrocyte apoptosis and local inflammation. Of note, there is no treatment for OA.

Objectives Previous data on collagen-induced arthritis (CIA) in mice have demonstrated that adrenomedullin (AM) and an AM-derived peptide (22-52AM) could modulate inflammation and chondrocyte apoptosis. Our purpose was to study the effect of AM) and 22-52AM on chondrocytes in vitro and in OA model in vivo. In one hand, we have investigated AM and AM receptor [Calcitonin Receptor Like Receptor (CLR)/Receptor Activating Modulated Protein (RAMP)] expression by articular chondrocytes under physiological (hypoxia) and OA (IL-1β) environment; in the other hand we brought evidence highlighting the effects of AM and 22-52 AM on cartilage breakdown and chondrocyte apoptosis in vitro and in vivo.

Methods In normoxia or hypoxia (physiological condition), ADMand its receptor expression was investigated in bovine articular chondrocytes (BAC) at the mRNA (RT-qPCR) and protein levels (EIA, immunolfluorescence). ADM and 22-52ADM anti-apoptotic effects were assessed on Fas-ligand (FasL)-mediated apoptosis using caspase-specific fluorogenic substrates. To assess the ADM anti-inflammatory effect on IL1β-stimulated chondrocytes, RT-qPCR analyses were performed to assess production of pro-inflammatory factors. Meniscectomized mice were injected IP 3 times a week during 8 weeks with PBS, ADM or 22-52ADM (1.2 µg/g). Joints were then prepared for histological analysis to quantify chondrocyte apoptosis (TUNEL) and cartilage degradation (Safranin-O).

Results Using immunofluorescence, we have demonstrated that CLR and RAMPs were more colocalized when chondrocytes were cultured in hypoxia, and especially in inflammatory environment. Coupled with AMPc measurements, those data suggest that the receptor is functional. Moreover, in such conditions, ADM secretion was significantly increased and exogenous ADM (10-6M) demonstrated anti-apoptotic activity. Nevertheless, ADM failed to modulate mRNA production of pro-inflammatory factors. Regarding joint degradation rate of meniscetomized mice, neither ADM nor the 22-52ADM have had a protective effect on apoptosis and chondrolysis.

Conclusions In « physiological environment », BAC were able to produce both ADM and functional receptor components. In addition, ADM treatment prevented FasL-induced apoptosis in hypoxia although its anti-inflammatory effect was not confirmed in these cells. Contrary to our expectations based on the CIA model, ADM or its derived peptide 22-52ADM administered systemically did not disclose any effect on OA progression. Direct intra-articular effects of ADM might be investigated.

Disclosure of Interest None Declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.