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

doi:10.1016/j.mam.2005.01.003

Molecular Aspects of Medicine

Volume 26, Issue 3, June 2005, Pages 169-179

https://doi.org/10.1016/j.mam.2005.01.003 Get rights and content

Abstract

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.

Section snippets

Articular cartilage constitutes a unique model for chondrocyte differentiation

Articular cartilage and cartilages that undergo mineralization (e.g. growth plate) are comprised of distinct chondrocytic cell types that are biochemically/genetically distinguishable even though they originate from a common chondroprogenitor cell (Fig. 1). For example, ACs, which can be termed ‘maturationally arrested’, primarily act to maintain the extracellular matrix by expressing collagen types II, VI, IX and XI and aggrecan (Buckwalter and Mankin, 1997). While these cells are

Chemically-induced OA in a chick articular cartilage model

Establishing a culture system that would facilitate the study of mechanisms that suppress or drive AC maturation became necessary to understand OA in various animal models. A previously established method to induce commitment/maturation of pluripotent cells involves treatment with 5-Azacytidine. Aza, which replaces cytidine bases in genomic DNA during replication, cannot be methylated by DNA methyltransferases and thus perturbs the methylation pattern of cytidines (CpG islands) present in

SMAD-mediated transcriptional signaling is disrupted during OA

Since it is hypothesized that OA arises as a result of inappropriate maturation of ACs (Pullig et al., 2000, Sandell et al., 2001, Sztrolovics et al., 2002, von der Mark et al., 1992), use of Aza-treated cells as an in vitro model will facilitate the major long term aim of identifying candidate causative mechanisms that are capable of abrogating maturational arrest in these cells (Zuscik et al., 2004). It is now well established that activation of the TGF-β receptor leads to the secondary

SMAD-independent transcriptional regulators of chondrocyte maturation

The integration of other signaling molecules to control chondrocyte differentiation downstream of the TGF-β superfamily members and the Ihh/PTHrP major players seems to be crucial for understanding the molecular pathways involved in regulating cartilage metabolism. Most of our effort has aimed at characterization of the transcriptional mechanisms downstream of these pathways. While PTHrP signaling is known to increase both cAMP and calcium levels in chondrocytes, with subsequent activation of

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

Abstract

Section snippets

Articular cartilage constitutes a unique model for chondrocyte differentiation

Chemically-induced OA in a chick articular cartilage model

SMAD-mediated transcriptional signaling is disrupted during OA

SMAD-independent transcriptional regulators of chondrocyte maturation

Dev. Biol.

Exp. Cell Res.

Dev. Biol.

Cell

J. Biol. Chem.

J. Orthop. Res.

Matrix Biol.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

Cell

Cytokine Growth Factor Rev.

Osteoarthritis Cartilage

Cell

Cytokine Growth Factor Rev.

Cytokine Growth Factor Rev.

Proc. Natl. Acad. Sci. USA

Cell Calcium

Arch. Biochem. Biophys.

Structure, function, and expression of the receptor for parathyroid hormone and parathyroid hormone-related peptide

Adv. Nephrol. Necker Hosp.

Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation

J. Cell Biol.

Bone morphogenetic protein (BMP) localization in developing human and rat growth plate, metaphysis, epiphysis, and articular cartilage

J. Histochem. Cytochem.

Disease-modifying activity of SB242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis

Arthritis Rheum.

TGF-β induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation

Nat. Cell Biol.

Articular cartilage

J. Bone Joint Surg.

A novel cell culture model of chondrocyte differentiation during mammalian endochondral ossification

J. Bone Miner. Res.

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