Bone morphogenetic protein (BMP) signalling plays a significant role during embryonic cartilage development and has been associated with osteoarthritis (OA) pathogenesis, being in both cases involved in triggering hypertrophy. Inspired by recent findings that BMP inhibition counteracts hypertrophic differentiation of human mesenchymal progenitors, we hypothesized that selective inhibition of BMP signalling would mitigate hypertrophic features in OA cartilage. First, a 3D in vitro OA micro-cartilage model was established using minimally expanded OA chondrocytes that was reproducibly able to capture OA-like hypertrophic features. BMP signalling was then restricted by means of two BMP receptor type I inhibitors, resulting in reduction of OA hypertrophic traits while maintaining synthesis of cartilage extracellular matrix. Our findings open potential pharmacological strategies for counteracting cartilage hypertrophy in OA and support the broader perspective that key signalling pathways known from developmental processes can guide the understanding, and possibly the mitigation, of adult pathological features.
Objective Cellular and molecular events occurring in cartilage regions close to injury are poorly investigated, but can possibly compromise the outcome of cell-based cartilage repair. In this study, key functional properties were assessed for cartilage biopsies collected from the central part of traumatic joint lesions ( central) and from regions surrounding the defect ( peripheral). These properties were then correlated with the quality of the initial cartilage biopsy and the inflammatory state of the joint. Design Cartilage samples were collected from knee joints of 42 patients with traumatic knee injuries and analyzed for cell phenotype (by reverse transcriptas-polymerase chain reaction), histological quality, cellularity, cell viability, proliferation capacity, and post-expansion chondrogenic capacity of chondrocytes (in pellet culture). Synovium was also harvested and analyzed for the expression of inflammatory cytokines. Results Cartilage quality and post-expansion chondrogenic capacity were higher in peripheral versus central samples. Differences between these 2 parameters were more pronounced in joints with high inflammatory features characterized by >100-fold difference in the mRNA levels of IL6 and IL8 in the corresponding synovium. Peripheral chondrocytes isolated from good- versus bad-quality biopsies expressed higher levels of collagen II/I and aggrecan/versican and lower levels of MMP13 and ADAMTS5. They also exhibited reduced proliferation and enhanced cartilage-forming capacity. Conclusions Chondrocytes at the periphery of traumatic lesions better maintain properties of healthy cartilage compared to those isolated from the center, even when derived from bad-quality tissues harvested from highly inflamed joints. Future studies are necessary to investigate the change of functional properties of peripheral chondrocytes over time.
Synovitis is common in knee OA patients and a known contributor to disease incidence and progression. Macrophages are the most common immune cell type present in this inflamed synovial tissue and expectedly contribute both directly and indirectly to OA progression through the induction of inflammatory mediators, growth factors and proteinases, resulting in enhanced cartilage degeneration and osteophyte formation. Furthermore, macrophage infiltration and soluble macrophage products may be associated with pain in OA, although data are somewhat controversial. OA synovium features macrophage heterogeneity, represented by the presence of subsets covering the broad spectrum of M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotypes, whose emergence corresponds to the cytokine profile found in OA patients. Conflicting results have been reported in both early and advanced OA concerning macrophage number, location, marker expression and cytokine profile, which may also be a consequence of the lack of universal definitions of disease stages and OA phenotypes. In this review, we summarize and discuss the positioning of synovial macrophages in knee OA in the context of pathogenesis, synovitis, and disease monitoring and as a target for therapeutic interventions.
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