Role of c‐fos in the regulation of type X collagen gene expression by PTH and PTHrP: Localization of a PTH/PTHrP‐responsive region in the human COL10A1 enhancer

Riemer, Silvia; Gebhard, Sonja; Beier, Frank; Pöschl, Ernst; Mark, Klaus von der

doi:10.1002/jcb.10260

Cited by 44 publications

(48 citation statements)

References 56 publications

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“…We, therefore, propose that PTHrP is one of the main candidate mediators of coculture-induced reduction of hypertrophy in our model. This is consistent with the established direct suppression of COL10A1 by PTHrP via a PTH/ PTHrP-responsive region in the human COL10A1 enhancer (39) and parallels the suggestion that PTHrP may mediate the suppression of AP activity and matrix mineralization in a coculture model of deep-zone with surface-zone bovine cartilage (30).…”

Section: Discussionsupporting

confidence: 88%

Human articular chondrocytes secrete parathyroid hormone–related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis

Fischer¹,

Dickhut²,

Rickert³

et al. 2010

Arthritis & Rheumatism

231

240

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Objective. The use of bone marrow-derived mesenchymal stem cells (MSCs) has shown promise in cell-based cartilage regeneration. A yet-unsolved problem, however, is the unwanted up-regulation of markers of hypertrophy, such as alkaline phosphatase (AP) and type X collagen, during in vitro chondrogenesis and the formation of unstable calcifying cartilage at heterotopic sites. In contrast, articular chondrocytes produce stable, nonmineralizing cartilage. The aim of this study was to address whether coculture of MSCs with human articular chondrocytes (HACs) can suppress the undesired hypertrophy in differentiating MSCs.Methods. MSCs were differentiated in chondrogenic medium that had or had not been conditioned by parallel culture with HAC pellets, or MSCs were mixed in the same pellet with the HACs (1:1 or 1:2 ratio) and cultured for 6 weeks. Following in vitro differentiation, the pellets were transplanted into SCID mice.Results. The gene expression ratio of COL10A1 to COL2A1 and of Indian hedgehog (IHH) to COL2A1 was significantly reduced by differentiation in HACconditioned medium, and less type X collagen protein was deposited relative to type II collagen. AP activity was significantly lower (P < 0.05) in the cells that had been differentiated in conditioned medium, and transplants showed significantly reduced calcification in vivo. In mixed HAC/MSC pellets, suppression of AP was dose-dependent, and in vivo calcification was fully inhibited. Chondrocytes secreted parathyroid hormonerelated protein (PTHrP) throughout the culture period, whereas PTHrP was down-regulated in favor of IHH up-regulation in control MSCs after 2-3 weeks of chondrogenesis. The main inhibitory effects seen with HACconditioned medium were reproducible by PTHrP supplementation of unconditioned medium.Conclusion. HAC-derived soluble factors and direct coculture are potent means of improving chondrogenesis and suppressing the hypertrophic development of MSCs. PTHrP is an important candidate soluble factor involved in this effect.Due to the limited self-repair capacity of articular cartilage and the lack of efficient pharmacologic treatments for chondral defects, cell-based approaches for articular cartilage regeneration have been developed. One of these approaches, autologous chondrocyte transplantation (ACT), has been used with encouraging clinical results (1-5). For ACT, chondrocytes are harvested by biopsy of a non-weight-bearing region of the damaged joint, expanded ex vivo, and then reinjected into the site of the defect. Among the limitations of ACT are a paucity of the cell source and tissue damage at the donor site, with the risk of emerging osteoarthritis. To overcome these problems, adult mesenchymal stem cells (MSCs) have been proposed as an alternative cell source. MSCs can be easily obtained from different sources, such as bone marrow (6,7) and adipose tissue (8), and possess good proliferation and differentiation potential, including differentiation into a chondrogenic phenotype (8,9).

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Section: Discussionsupporting

confidence: 88%

Human articular chondrocytes secrete parathyroid hormone–related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis

Fischer¹,

Dickhut²,

Rickert³

et al. 2010

Arthritis & Rheumatism

231

240

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“…Binding around Col10a1 highlighted a previously identified hypertrophic DNA enhancer module 4 kb upstream of Col10a1 that is sufficient to direct hypertrophic chondrocyte-restricted reporter gene expression in vivo (Fig. 2F) (Chambers et al, 2002;Gebhard et al, 2004;Leung et al, 2011;Li et al, 2011;Riemer et al, 2002;Zheng et al, 2009).…”

Section: Co-occupancy Of the Chondrocyte Genome By Sox9 And Junmentioning

confidence: 75%

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

Ohba

Hojo

et al. 2016

Development

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An analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif. Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun-and Sox9-bound regions throughout the chondrocyte genome, reflecting direct binding of each factor to the same enhancers and a potential for protein-protein interactions within AP-1-and Sox9-containing complexes. In vitro reporter analysis indicated that direct co-binding of Sox9 and AP-1 at target motifs promoted gene activity. By contrast, where only one factor can engage its DNA target, the presence of the other factor suppresses target activation consistent with protein-protein interactions attenuating transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 confirmed the requirement of Sox9 for hypertrophic chondrocyte development, and in vitro and ex vivo analyses showed that AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model in which AP-1 family members contribute to Sox9 action in the transition of chondrocytes to the hypertrophic program.

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“…Consistent with its role in skeletal development, Runx2-knockout mice develop a cartilage-only skeleton with no bone components (Komori et al, 1997;Otto et al, 1997). In addition to RUNX2 as a positive regulator, other transcription factors such as c-FOS and DLX also regulate Col10a1 expression in a tissue-specific manner (Hassan et al, 2004;Riemer et al, 2002). Therefore, detailed analysis on the regulation of Col10a1 expression in both osteogenic and chondro-genic lineages may provide valuable information regarding the upstream regulators of Col10a1 acting specifically to induce either bone structures or cartilages.…”

Section: Introductionmentioning

confidence: 95%

Establishment of a Bone-Specific col10a1:GFP Transgenic Zebrafish

Kim

Lee

Jung

et al. 2013

Molecules and Cells

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During skeletal development, both osteogenic and chondrogenic programs are initiated from multipotent mesenchymal cells, requiring a number of signaling molecules, transcription factors, and downstream effectors to orchestrate the sophisticated process. Col10a1, an important downstream effector gene, has been identified as a marker for maturing chondrocytes in higher vertebrates, such as mammals and birds. In zebrafish, this gene has been shown to be expressed in both osteoblasts and chondrocytes, but no study has reported its role in osteoblast development. To initially delineate the osteogenic program from chondrogenic lineage development, we used the zebrafish col10a1 promoter to establish a transgenic zebrafish expressing a GFP reporter specifically in osteoblast-specific bone structures that do not involve cartilaginous programs. A construct harboring a ~2.2-kb promoter region was found to be sufficient to drive the reporter gene in osteoblast-specific bone structures within the endogenous col10a1 expression domain, confirming that separable cis-acting elements exist for distinct cell type-specific expression of col10a1 during zebrafish skeletal development. The ~2.2-kb col10a1:GFP transgenic zebrafish marking only bone structures derived from osteoblasts will undoubtedly be an invaluable tool for identifying and characterizing molecular events driving osteoblast development in zebrafish, which may further provide a differential mechanism where col10a1 is involved in the development of chondrocytes undergoing maturation in other vertebrate systems.

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Role of c‐fos in the regulation of type X collagen gene expression by PTH and PTHrP: Localization of a PTH/PTHrP‐responsive region in the human COL10A1 enhancer

Cited by 44 publications

References 56 publications

Human articular chondrocytes secrete parathyroid hormone–related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis

Human articular chondrocytes secrete parathyroid hormone–related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

Establishment of a Bone-Specific col10a1:GFP Transgenic Zebrafish

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