Early intra-articular injection of mesenchymal stem cells prevents synovial inflammation after medial meniscal release in a rabbit model of osteoarthritis

Abstract

Purpose: Osteoarthritis (OA) is characterized by a catabolic and inflammatory joint environment. One of the main objective in the management of OA is to dampen local inflammation in an attempt to slow down cartilage degradation process and to relieve pain. Until recently, Mesenchymal Stromal Cell (MSC) therapies for OA treatment have mainly relied on their chondrogenic properties for cartilage repair. The anti-inflammatory and immunomodulatory properties of Umbilical Cord-Derived MSC (UC-MSC) has been rarely studied in the context of the onset of the disease. In the present study, we investigated the anti-inflammatory and anticatabolic effects of UC-MSC in a rabbit model of first stage mild OA.We examined the differential ability of an early or delayed intra-articular (IA) injection of UC-MSC in preventing synovial inflammation, one of the first events leading ultimately to cartilage damage. The interactions between MSC and the synovial membrane with regards to MSC antiinflammatory potentials were evaluated especially by analyses of the expression of genes related to inflammation and matrix turnover. The nature of the effects of UC-MSC on stimulated synoviocytes were further investigated in vitro. Methods: Medial meniscal release (MMR) was performed in rabbit knee joints (day 0). A single early or delayed intra-articular (IA) injection of UC-MSC was realized (day 3 or 15). At day 56, gross morphology, Equilibrium Partitioning of an Ionic Contrast agent via micro-CT (EPIC-μCT) and histology were performed to grade OA lesions. Gene expression of inflammatory cytokines and metalloproteases was measured, in synovial tissue harvested from the OA knees. In order to study the paracrine effects of UC-MSC, control rabbit primary synoviocytes were incubated with UC-MSC-conditioned medium or control medium under pro-inflammatory stimulus for 48 h (Il-1β (10ng/ml)). Results: As expected, at day 56, MMR procedure leads to changes consistent with earlyOAin the medial compartment of the rabbit knee joints. Cartilage fibrillation, inflammatory cytokines and metalloproteases gene expressions were lower in the early IA group than in the delayed group. OA synovium gene expression analysis showed a reduction in the expression of both the inflammatory cytokines (IL1β, TNFα) and the metalloproteases (MMP-1, -3, -13) in the early-injected group compared to the MMR group. UC-conditioned medium exerted antiinflammatory and anti-catabolic effects synoviocytes stimulated with Il-1β. These results confirmed UC-MSC possess paracrine activity that target stimulated synoviocytes. Conclusions: This study shows the efficiency of a single early IA injection in preventing OA signs in rabbit knee following MMR. Early UC-MSC IA injection might be more efficient to reduce inflammation and prevents OA progression than delayed UC-MSC IA injection.