Abstract
Osteoarthritis (OA) is characterized by a slowly progressing, irreversible loss of articular cartilage. Tissue engineering approaches for cartilage regeneration include stem cell-based strategies but not much is known about their repair capacity in an OA microenvironment. The aim of the present study was to identify factors regulating collagen expression during chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSC) in an OA microenvironment. Coculture with OA cartilage induced miR-29b expression in BMSC which inhibited collagen I and III expression. Elevated miR-29b expression resulted in higher caspase 3/7 activity and promoted apoptosis of BMSC in part by directly inhibiting the anti-apoptotic proteins Bcl-2 and Mcl-1. Stimulation with IFN-γ induced miR-29b expression in BMSC. Our results suggest that miR-29b affects BMSC-based OA cartilage regeneration because expression of collagen III, mainly produced by undifferentiated BMSC, and collagen I, a marker for dedifferentiated chondrocytes, are inhibited by miR-29b thus influencing composition of the newly formed ECM. This might be critical to avoid formation of inferior fibrocartilage instead of hyaline cartilage. Furthermore, higher miR-29b expression promotes apoptosis either preventing excessive cell growth or reducing the number of BMSC undergoing chondrogenesis. Thus, miR-29b has both supportive but possibly also unfavourable effects on BMSC-based OA cartilage regeneration.
Highlights
Osteoarthritis (OA) is a common, multi-factorial, slowly progressing and irreversible degenerative disorder affecting entire synovial joints mostly of hands, knees and hips
bone marrow-derived mesenchymal stem cells (BMSC) embedded in fibrin gels subjected to chondrogenic differentiation on top of OA cartilage explants for 7 and 28 days, exhibited lower COL1A1 and COL3A1 and higher gene expression levels of mature miR-29b-3p compared to BMSC kept in monoculture without cartilage explants (Fig. 1a)
OA subchondral bone explants had no significant effect on miR-29b, COL1A1, COL3A1 and COL2A1 gene expression of cocultured BMSC subjected to chondrogenic differentiation after 7 and 28 days compared to monocultured cells (Fig. 1b)
Summary
Osteoarthritis (OA) is a common, multi-factorial, slowly progressing and irreversible degenerative disorder affecting entire synovial joints mostly of hands, knees and hips. Cultured human bone marrow-derived mesenchymal stem cells (BMSC) possess chondrogenic differentiation potential[8] but not much is known about their capacity to form cartilage under the influence of the OA microenvironment if they are isolated from OA patients, expanded in vitro and reimplanted into a diseased joint. Coculture with OA cartilage explants resulted in reduced collagen gene and protein expression in chondrogenically differentiating BMSC compared to monocultured cells. If BMSC undergo chondrogenic differentiation in coculture with OA cartilage explants, both collagen I and III expression become reduced compared to BMSC kept in monocultures[15]. One possible mechanism for the downregulation of collagen I and III expression found in BMSC cocultured with OA cartilage might be via microRNAs (miR), short non-coding RNAs which regulate gene expression post-transcriptionally[23]. Direct binding of miR-29b to the mRNA within the 3′-UTR of COL1A1 and COL3A1 leading to mRNA degradation or preventing its translation is confirmed by luciferase reporter gene assays e.g. by Steele, et al.[35]
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