Biology of signalling receptors in human articular chondrocytes. Implications for chondrogenesis and cartilage repair.

Abstract

Articular cartilage is the thin avascular tissue covering the ends of adjacent bones that provides frictionless movement to the skeleton. Cartilage injuries are frequent, but due to its avascular nature the cartilage of skeletally matured individuals has a poor healing capacity. Degenerative diseases such as osteoarthritis (OA), is characterised by the gradual destruction of articular cartilage, typically affecting hand-, hip- and knee joints. In the orthopaedic field, there is a growing interest in transitioning from joint-replacement surgery in end-stage disease to biological repair techniques applied at an earlier stage. Short- and mid-term clinical outcomes of these cell-based therapies are promising, but the long-term results are unsatisfactory. The field is so far progressing based on trial-error approaches and there is an urgent need to increase our understanding on the biological principles governing tissue homeostasis and disease development. Hence, the aim of this thesis was to investigate cell-signalling receptors in chondrocytes in the context of chondrogenesis and cartilage repair. We found novel evidence of functional leukotriene B₄ receptors expressed in chondrocytes, but no clear read-outs upon stimulation of the receptors with their cognate ligand. The vitamin D receptor is expressed at very low levels in cartilage, but its expression is enhanced in monolayer cultures and under inflammatory conditions. We were able to demonstrate that the chondrocyte exhibit 1α-hydroxylase activity facilitating active hormone production. In dedifferentiated chondrocytes, vitamin D promoted cell proliferation, but the overall effect on chondrogenesis was unfavourable. In the last study, we have searched for potential biomarkers of chondrogenesis, with focus on cell adhesion molecules and other cell surface receptors. Our data shows that all studied cell-cell and cell-matrix receptors are not good predictors of chondrogenesis. Of note, high throughput proteomic analyses uncovered the potential of prolyl 4-hydroxylase, an enzyme implicated in collagen biosynthesis, as a predictor of intrinsic chondrogenesis.