Transcriptional regulation of chondrocyte maturation: Potential involvement of transcription factors in OA pathogenesis

The Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, United States.
Molecular Aspects of Medicine (Impact Factor: 10.24). 07/2005; 26(3):169-79. DOI: 10.1016/j.mam.2005.01.003
Source: PubMed


The principle function of articular cartilage is to provide a low friction load-bearing surface that facilitates free movement of joints. Maintenance of this surface depends on the maturational arrest of chondrocytes before terminal hypertrophic differentiation occurs [Exp. Cell Res. 216 (1995) 191; Osteoarthritis Cartilage 7 (1999) 389; J. Cell Biol. 139 (1997) 541; J. Cell Biol. 145 (1999) 783]. In contrast to endochondral ossification which involves a programmed process of chondrocyte maturation culminating in terminal hypertrophy and mineralization [Nat. Genet. 9 (1995) 15], articular chondrocytes (ACs) are constrained from completing the maturational program as evidenced by a lack of type X collagen (colX) and alkaline phosphatase expression [Arthritis Res. 3 (2001) 107; Biochem. J. 362 (2002) 473]. Also, ACs are not responsive to factors that impact the maturational process, including bone morphogenetic protein-2 (BMP-2), a potent stimulator of chondrocyte maturation [J. Orthop. Res. 14 (1996) 937]. Factors that constrain AC maturation are only relieved under unique circumstances such as in osteoarthritis (OA), where proliferation and an increase in the expression of hypertrophic hallmarks indicates that the cells have differentiated into a mature phenotype [Calcif. Tissue Int. 63 (2000) 230]. OA may thus involve the functional loss of mechanisms that arrest articular cartilage differentiation. Responsiveness to various growth or systemic factors translates into activation or repression of specific genes through transcriptional mediators. Understanding the downstream mechanisms involved in this process is of paramount importance. Thus, unraveling the molecular interplay between various factors that regulate chondrocyte maturation during OA occurrence and progression is the main focus of ongoing efforts.

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    • "Polyamines in regenerative medicine in orthopedics 719 maturational arrest'' (Drissi et al. 2005) and downstream progression along the normal chondrocyte differentiation pathway to hypertrophy and terminal differentiation. Accordingly, osteoarthritic ''hypertrophic'' articular chondrocytes acquire the expression of TG2 (Tarantino et al. 2013). "
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    ABSTRACT: The first step in skeleton development is the condensation of mesenchymal precursors followed by any of two different types of ossification, depending on the type of bone segment: in intramembranous ossification, the bone is deposed directly in the mesenchymal anlagen, whereas in endochondral ossification, the bone is deposed onto a template of cartilage that is subsequently substituted by bone. Polyamines and polyamine-related enzymes have been implicated in bone development as global regulators of the transcriptional and translational activity of stem cells and pivotal transcription factors. Therefore, it is tempting to investigate their use as a tool to improve regenerative medicine strategies in orthopedics. Growing evidence in vitro suggests a role for polyamines in enhancing differentiation in both adult stem cells and differentiated chondrocytes. Adipose-derived stem cells have recently proved to be a convenient alternative to bone marrow stromal cells, due to their easy accessibility and the high frequency of stem cell precursors per volume unit. State-of-the-art "prolotherapy" approaches for skeleton regeneration include the use of adipose-derived stem cells and platelet concentrates, such as platelet-rich plasma (PRP). Besides several growth factors, PRP also contains polyamines in the micromolar range, which may also exert an anti-apoptotic effect, thus helping to explain the efficacy of PRP in enhancing osteogenesis in vitro and in vivo. On the other hand, spermidine and spermine are both able to enhance hypertrophy and terminal differentiation of chondrocytes and therefore appear to be inducers of endochondral ossification. Finally, the peculiar activity of spermidine as an inducer of autophagy suggests the possibility of exploiting its use to enhance this cytoprotective mechanism to counteract the degenerative changes underlying either the aging or degenerative diseases that affect bone or cartilage.
    Amino Acids 11/2013; 46(3). DOI:10.1007/s00726-013-1607-9 · 3.29 Impact Factor
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    • "Indeed, hypertrophic chondrocytes undergo apoptosis leading to a dysregulation of matrix repair mechanism [11]. The role of ROS is nowadays well established in this terminal differentiation [12], [13], [14]. "
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    ABSTRACT: Interleukin-1β (IL-1β) activates the production of reactive oxygen species (ROS) and secretion of MMPs as well as chondrocyte apoptosis. Those events lead to matrix breakdown and are key features of osteoarthritis (OA). We confirmed that in human C-20/A4 chondrocytes the NADPH oxidase Nox4 is the main source of ROS upon IL-1β stimulation. Since heme molecules are essential for the NADPH oxidase maturation and activity, we therefore investigated the consequences of the modulation of Heme oxygenase-1 (HO-1), the limiting enzyme in heme catabolism, on the IL-1β signaling pathway and more specifically on Nox4 activity. Induction of HO-1 expression decreased dramatically Nox4 activity in C-20/A4 and HEK293 T-REx™ Nox4 cell lines. Unexpectedly, this decrease was not accompanied by any change in the expression, the subcellular localization or the maturation of Nox4. In fact, the inhibition of the heme synthesis by succinylacetone rather than heme catabolism by HO-1, led to a confinement of the Nox4/p22(phox) heterodimer in the endoplasmic reticulum with an absence of redox differential spectrum highlighting an incomplete maturation. Therefore, the downregulation of Nox4 activity by HO-1 induction appeared to be mediated by carbon monoxide (CO) generated from the heme degradation process. Interestingly, either HO-1 or CO caused a significant decrease in the expression of MMP-1 and DNA fragmentation of chondrocytes stimulated by IL-1β. These results all together suggest that a modulation of Nox4 activity via heme oxygenase-1 may represent a promising therapeutic tool in osteoarthritis.
    PLoS ONE 06/2013; 8(6):e66478. DOI:10.1371/journal.pone.0066478 · 3.23 Impact Factor
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    • "Of these, RUNX2 and ALPL were expressed at higher levels in BM-MSC derived chondrocytes, while the expression of MMP13 was very low in both cell populations by RT-qPCR, and not discernible in the microarray assay. Many of the processes associated with chondrocyte hypertrophy, including chondrocyte apoptosis and ECM mineralization have been suggested to also be involved in OA pathogenesis [21], [23], [35], [36], [45]. We have seen no evidence of apoptosis or mineralization occurring during 6–8 week cultures of BM-MSCs exposed to chondrogenic differentiation medium in alginate (A. "
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    ABSTRACT: Lesions of hyaline cartilage do not heal spontaneously, and represent a therapeutic challenge. In vitro engineering of articular cartilage using cells and biomaterials may prove to be the best solution. Patients with osteoarthritis (OA) may require tissue engineered cartilage therapy. Chondrocytes obtained from OA joints are thought to be involved in the disease process, and thus to be of insufficient quality to be used for repair strategies. Bone marrow (BM) derived mesenchymal stem cells (MSCs) from healthy donors may represent an alternative cell source. We have isolated chondrocytes from OA joints, performed cell culture expansion and tissue engineering of cartilage using a disc-shaped alginate scaffold and chondrogenic differentiation medium. We performed real-time reverse transcriptase quantitative PCR and fluorescence immunohistochemistry to evaluate mRNA and protein expression for a range of molecules involved in chondrogenesis and OA pathogenesis. Results were compared with those obtained by using BM-MSCs in an identical tissue engineering strategy. Finally the two populations were compared using genome-wide mRNA arrays. At three weeks of chondrogenic differentiation we found high and similar levels of hyaline cartilage-specific type II collagen and fibrocartilage-specific type I collagen mRNA and protein in discs containing OA and BM-MSC derived chondrocytes. Aggrecan, the dominant proteoglycan in hyaline cartilage, was more abundantly distributed in the OA chondrocyte extracellular matrix. OA chondrocytes expressed higher mRNA levels also of other hyaline extracellular matrix components. Surprisingly BM-MSC derived chondrocytes expressed higher mRNA levels of OA markers such as COL10A1, SSP1 (osteopontin), ALPL, BMP2, VEGFA, PTGES, IHH, and WNT genes, but lower levels of MMP3 and S100A4. Based on the results presented here, OA chondrocytes may be suitable for tissue engineering of articular cartilage.
    PLoS ONE 05/2013; 8(5):e62994. DOI:10.1371/journal.pone.0062994 · 3.23 Impact Factor
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