Evaluation of Allogeneic Bone-Marrow-Derived and Umbilical Cord Blood-Derived Mesenchymal Stem Cells to Prevent the Development of Osteoarthritis in An Equine Model.

Osteoarthritis (OA) is a significant cause of pain in both humans and horses with a high socio-economic impact. The horse is recognized as a pertinent model for human OA. In both species, regenerative therapy with allogeneic mesenchymal stem cells (MSCs) appears to be a promising treatment but, to date, no in vivo studies have attempted to compare the effects of different cell sources on the same individuals. The objective of this study is to evaluate the ability of a single blinded intra-articular injection of allogeneic bone-marrow (BM) derived MSCs and umbilical cord blood (UCB) derived MSC to limit the development of OA-associated pathological changes compared to placebo in a post-traumatic OA model applied to all four fetlock joints of eight horses. The effect of the tissue source (BM vs. UCB) is also assessed on the same individuals. Observations were carried out using clinical, radiographic, ultrasonographic, and magnetic resonance imaging methods as well as biochemical analysis of synovial fluid and postmortem microscopic and macroscopic evaluations of the joints until Week 12. A significant reduction in the progression of OA-associated changes measured with imaging techniques, especially radiography, was observed after injection of bone-marrow derived mesenchymal stem cells (BM-MSCs) compared to contralateral placebo injections. These results indicate that allogeneic BM-MSCs are a promising treatment for OA in horses and reinforce the importance of continuing research to validate these results and find innovative strategies that will optimize the therapeutic potential of these cells. However, they should be considered with caution given the low number of units per group.

Correction to: Induced membrane maintains its osteogenic properties even when the second stage of Masquelet's technique is performed later.

The original version of this article unfortunately contained a mistake. The presentation and legends of Figs. 4 and 5 were incorrect. The corrected versions are given below. The original article has been corrected.

Induced membrane maintains its osteogenic properties even when the second stage of Masquelet's technique is performed later.

PURPOSE: Previous clinical studies have shown the effectiveness of bone repair using two-stage surgery called the induced membrane (IM) technique. The optimal wait before the second surgery is said to be 1 month. We have been successfully performing the IM technique while waiting an average of 6 months to carry out the second stage. We hypothesised that the IM maintains its beneficial capabilities, even at a later second stage, and that there is no relation between the speed of bone union and the wait between the first and second stage. We sought to explore the biological properties of 'older' IMs sampled to substantiate our clinical observations. METHODS: Thirty-four patients with a critical size defect were treated with the IM technique. In seven of these patients, pieces of the IM were collected 4.2-14.7 months after the first surgery. IM-derived cell phenotype and osteogenic potential were investigated using in vitro studies (n = 4) while IM nature and function were investigated by histology and immunohistochemistry (n = 3). RESULTS: The median wait before the second surgery was 5.8 months [range 1.2-14.7] and bone healing occurred at 7.6 months [range 2.5-49.9] for 26 patients. IMs aged 4.2-14.7 months contained mesenchymal stromal cells with in vitro osteogenic potential and corresponded to a multipotent tissue with osteogenic and chondrogenic capabilities contributing to osteogenesis over time. CONCLUSION: This preliminary study suggests the IM retains its powerful osteogenic properties over time and that waiting longer between the two surgeries does not delay bone union.

Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter.

Type II collagen is composed of alpha1(II) chains encoded by the COL2A1 gene. Alteration of this cartilage marker is a common feature of osteoarthritis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that needs a soluble form of receptor called sIL-6R to exert its effects in some cellular models. In that case, sIL-6R exerts agonistic action. This mechanism can make up for the partial or total absence of membrane-anchored IL-6 receptors in some cell types, such as chondrocytes. Our study shows that IL-6, sIL-6R, or both inhibit type II collagen production by rabbit articular chondrocytes through a transcriptional control. The cytokine and/or sIL-6R repress COL2A1 transcription by a -63/-35 sequence that binds Sp1.Sp3. Indeed, IL-6 and/or sIL-6R inhibit Sp1 and Sp3 expression and their binding activity to the 63-bp promoter. In chromatin immunoprecipitation experiments, IL-6.sIL-6R induced an increase in Sp3 recruitment to the detriment of Sp1. Knockdown of Sp1.Sp3 by small interference RNA and decoy strategies were found to prevent the IL-6- and/or sIL-6R-induced inhibition of COL2A1 transcription, indicating that each of these Sp proteins is required for down-regulation of the target gene and that a heterotypic Sp1.Sp3 complex is involved. Additionally, Sp1 was shown to interact with Sp3 and HDAC1. Indeed, overexpression of a full-length Sp3 cDNA blocked the Sp1 up-regulation of the 63-bp COL2A1 promoter activity, and by itself, inhibits COL2A1 transcription. We can conclude that IL-6, sIL-6R, or both in combination decrease both the Sp1.Sp3 ratio and DNA-binding activities, thus inhibiting COL2A1 transcription.