J Bone Metab.  2017 Aug;24(3):147-153. 10.11005/jbm.2017.24.3.147.

Regulation of Cartilage Development and Diseases by Transcription Factors

• Nishimura
• Hata K
• Takahata Y
• Murakami T
• Nakamura E
• Yagi H

• KMID: 2415952
• DOI: http://doi.org/10.11005/jbm.2017.24.3.147

Abstract

Genetic studies and molecular cloning approaches have been successfully used to identify several transcription factors that regulate the numerous stages of cartilage development. Sex-determining region Y (SRY)-box 9 (Sox9) is an essential transcription factor for the initial stage of cartilage development. Sox5 and Sox6 play an important role in the chondrogenic action of Sox9, presumably by defining its cartilage specificity. Several transcription factors have been identified as transcriptional partners for Sox9 during cartilage development. Runt-related transcription factor 2 (Runx2) and Runx3 are necessary for hypertrophy of chondrocytes. CCAAT/enhancer-binding protein β (C/EBPβ) and activating transcription factor 4 (ATF4) function as co-activators for Runx2 during hypertrophy of chondrocytes. In addition, myocyte-enhancer factor 2C (Mef2C) is required for initiation of chondrocyte hypertrophy, presumably by functioning upstream of Runx2. Importantly, the pathogenic roles of several transcription factors in osteoarthritis have been demonstrated based on the similarity of pathological phenomena seen in osteoarthritis with chondrocyte hypertrophy. We discuss the importance of investigating cellular and molecular properties of articular chondrocytes and degradation mechanisms in osteoarthritis, one of the most common cartilage diseases.

Keyword

Cartilage; Chondrocytes; Osteoarthritis; Transcription factors

MeSH Terms

Activating Transcription Factor 4
Cartilage Diseases
Cartilage*
Chondrocytes
Cloning, Molecular
Hypertrophy
Osteoarthritis
Sensitivity and Specificity
Transcription Factors*
Activating Transcription Factor 4
Transcription Factors

Figure

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  Fig. 1 Regulation of endochondral ossification by transcription factors. Sex-determining region Y (SRY)-box 9 (Sox9) and Sox5/6/9 promotes commitment of mesenchymal cells into chondrocytes and chondrocyte differentiation, while Sox9 negatively regulates the late stage of endochondral ossification. Myocyte-enhancer factor 2C (Mef2C), runt-related transcription factor 2/3 (Runx2/3) and osterix regulate hypertrophy of chondrocytes, and calcification and degradation of cartilage matrices. Histone deacetylase 4 (Hdac4) antagonizes function of Mef2c.

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  Fig. 2 Negative-regulation of the late stage of endochondral ossification by Sex-determining region Y (SRY)-box 9 (Sox9) and Indian hedgehog (Ihh)/parathyroid hormone-related protein (PTHrP) loop. Sox9 and Ihh/Gli2 signaling cooperatively inhibit chondrocyte hypertrophy through upregulation of PTHrP, in which forkhead box C1 (Foxc1) is also involved. On the hand, Sox9 suppresses vascular invasion into cartilage by inhibiting vascular endothelial growth factor (VEGF) expression.

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  Fig. 3 Regulation of Sex-determining region Y (SRY)-box 9 (Sox9) function during cartilage development. Transcriptional partners for Sox9, p54nrb, AT-rich interactive domain 5A (Arid5a), Arid5b/PHD finger protein 2 (Phf2), zinc finger protein 219 (Znf219), and WW domain containing E3 ubiquitin protein ligase 2 (Wwp2), conduct chondrogenic action of Sox9.

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  Fig. 4 Synergistic role of runt-related transcription factor 2 (Runx2) and Indian hedgehog (Ihh)/Gli2 signaling in regulation of chondrocyte maturation. Runx2 and Ihh/Gli2 signaling synergistically regulate chondrocyte maturation by interacting with activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein beta (C/EBPβ). Cbfβ, core binding factor β.

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  Fig. 5 Involvement of transcription factors in pathogenesis of osteoarthritis. Runt-related transcription factor 2 (Runx2), hypoxia inducible factor 2α (HIF2α) and p63 are involved in pathogenesis of osteoarthritis. CCAAT/enhancer-binding protein β (C/EBPβ) is also potential pathogenic factor of osteoarthritis though interaction with Runx2. MMP13, matrix metalloproteinase 13.

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