In relation to regenerative therapies in osteoarthritis and cartilage repair, mesenchymal stromal cells (MSCs) have immunomodulatory functions and influence macrophage behaviour. Macrophages exist as a spectrum of pro-(M1) and anti-(M2) inflammatory phenotypic subsets. In the context of cartilage repair, we investigated MSC-macrophage crosstalk, including specifically the priming of cartilage cells by macrophages to achieve a regenerative rather than fibrotic outcome. Human monocytes were isolated from blood cones and differentiated towards M1 and M2 macrophages. Monocytes (Mo), M1 and M2 macrophages were cultured directly and indirectly (trans-well system) with human bone marrow derived MSCs. MSCs were added during M1 polarisation and separately to already induced M1 cells. Outcomes (M1/M2 markers and ligands/receptors) were evaluated using RT-qPCR and flow cytometry. Influence on chondrogenesis was assessed by applying M1 and M2 macrophage conditioned media (CM) sequentially to cartilage derived cells (recapitulating an acute injury environment). RT-qPCR was used to evaluate chondrogenic/fibrogenic gene transcription. The ratio of M2 markers (CD206 or CD163) to M1 markers (CD38) increased when MSCs were added to Mo/M1 macrophages, regardless of culture system used (direct or indirect). Pro-inflammatory markers (including TNFβ) decreased. CXCR2 expression by both M1 macrophages and MSCs decreased when MSCs were added to differentiated M1 macrophages in transwell. When adding initially M1 CM (for 12 hours) followed by M2 CM (for 12 hours) sequentially to chondrocytes, there was a significant increase of Aggrecan and Collagen type 2 gene expression and decrease in fibroblastic cell surface markers (PDPN/CD90). Mo/M1 macrophages cultured with MSCs, directly or indirectly, are shifted towards a more M2 phenotype. Indirect culture suggests this effect can occur via soluble signaling mediators. Sequential exposure of M1CM followed by M2CM to chondrocytes resulted in increased chondrogenic and reduced fibrotic gene expression, suggesting that an acute pro-inflammatory stimulus may prime chondrocytes before repair.

Abstract

This was a retrospective study of registry data from a National Orthopaedic Hospital for all THRs with 10-year follow-up data. Inclusion criteria were all THRs with a minimum of 10-year follow-up data. All metal-on-metal (MoM) THRs and MoM resurfacings were excluded from the analysis due to the high rate of revision associated with these bearings. Univariate and multivariate analyses controlling for confounding variables were performed to compare outcomes. A total of 1,697 THRs were performed in 1,553 patients. The four significant predictors for revision were fixation type (p<0.01), surface bearing type (p<0.01), age (P<0.05) and head size (p<0.05). Gender, BMI and approach had no effect on revision rates. The lowest 10-year all-cause revision rates were seen in cemented THRs at 1.7%. Ceramic-on-poly bearings had the lowest revision rate at only 1.2%. Metal-on-poly bearings had a 1.7% revision rate. Ceramic on ceramic bearings had a 7.1% revision rate with 1 revision for squeak and 1 revision for ceramic head fracture. The causes for revision in order of decreasing frequency were as follows: Infection (n=13, 0.7%), dislocation (n=7, 0.4%), periprosthetic fracture (n=3, 0.2%) and aseptic loosening (n=2, 0.1%). There were 2 re-revisions at 10 years in total. The smaller 22.225mm head sizes had a significantly lower revision rate than other head sizes (p<0.05). Ceramic-on-poly bearings, cemented fixation and smaller head sizes perform better in the experience of this registry. However, with multivariate analysis, these differences were shown to be insignificant.