BMP signaling stimulates chondrocyte maturation and the expression of Indian hedgehog

Grimsrud, Christopher D.; Romano, P. R.; D’Souza, Mary; Puzas, J. Edward; Schwarz, Edward M.; Reynolds, Paul; Roiser, Randy N.; O’Keefe, Regis J.

doi:10.1016/s0736-0266(00)00017-6

Cited by 105 publications

(83 citation statements)

References 37 publications

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“…Hedgehog signaling seems to interact with BMP signaling in regulation of several systems (Murtaugh et al 1999, Pathi et al 1999, Grimsrud et al 2001, and Cbfa1 expression can be induced by BMPs in C3H10T1/2 fibroblasts (Ducy et al 1997). We also observed that BMP enhances proliferation and alkaline phosphatase activity in chondrocytes.…”

Section: Figuresupporting

confidence: 58%

Hedgehog signaling enhances core-binding factor a1 and receptor activator of nuclear factor-kappaB ligand (RANKL) gene expression in chondrocytes

Takamoto

Tsuji

Yamashita

et al. 2003

Journal of Endocrinology

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Hedgehog signaling is considered to play a crucial role in chondrogenesis by regulation through a network of cytokine actions, which is not fully understood. We examined the effect of hedgehog signaling on the expression of core-binding factor a1 (Cbfa1), a critical transcription factor for the development of bone and cartilage. Primary chondrocytes prepared from the costal cartilage of newborn mice were treated with N-terminal fragment of recombinant murine sonic hedgehog (rmShh-N). Northern blot analysis indicated that Cbfa1 mRNA expression levels in the chondrocyte cultures were elevated by the treatment with rmShh-N. rmShh-N treatment enhanced 1·8 kb Cbfa1 promoter activity in chondrocytes, suggesting the presence of transcriptional control. As Cbfa1-binding site(s) have been located in the promoter of the receptor activator of nuclear factor-B (RANK) ligand (RANKL) gene, we also examined RANKL expression. rmShh-N treatment upregulated RANKL and RANK mRNA expression levels in chondrocytes. Interestingly, RANKL suppressed the hedgehog enhancement of alkaline phosphatase activity in chondrocytes, suggesting the presence of a link between these signaling molecules. We conclude that hedgehog signaling activates Cbfa1 gene expression through its promoter in chondrocytes, and also activates and interacts with RANKL to maintain cartilage development.

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Section: Figuresupporting

confidence: 58%

Hedgehog signaling enhances core-binding factor a1 and receptor activator of nuclear factor-kappaB ligand (RANKL) gene expression in chondrocytes

Takamoto

Tsuji

Yamashita

et al. 2003

Journal of Endocrinology

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“…As noted in the previous section, BMPs can regulate Ihh expression in pre-hypertrophic chondrocytes [Grimsrud et al, 2001]. While the mechanism of BMP regulation of Ihh is not known, evidence in both primary chondrocytes as well as chondrocytic cell lines suggest that both Smad proteins and the transcription factor Runx2 could be involved.…”

Section: Stimulators Of Ihh Expressionmentioning

confidence: 86%

Indian hedgehog: Its roles and regulation in endochondral bone development

Lai

Mitchell

2005

J of Cellular Biochemistry

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Normal endochondral bone development requires the coordination of chondrocyte proliferation and differentiation. Indian hedgehog (Ihh) is a morphogen produced by chondrocytes in the early stage of terminal differentiation and plays several key roles in this process. Ihh regulates growth of adjacent proliferative chondrocytes and can also regulate the rate of differentiation of chondrocytes indirectly through its stimulation of parathyroid hormonerelated protein (PTHrP). In this review, we focus on recent studies that have identified new functions of Ihh and how Ihh itself is being regulated.

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“…Tagariello et al (8) have shown that Ucma expression in the developing limb is Indian hedgehog independent. To investigate a potential regulatory effect on Ucma expression by BMP factors, which have been shown to promote chondrocyte maturation toward the hypertrophic phenotype in vitro and in vivo we treated chondrogenic MC615 cells and primary murine rib chondrocytes with increasing amounts of BMP-2 for 24 h (22). Northern blot analysis revealed a dose-dependent repression of Ucma mRNA expression in response to BMP-2 in both MC615 cells and primary chondrocytes (Fig.…”

Section: Bmp-2 Represses Ucma Transcription In Chondrogenic Cells-mentioning

confidence: 97%

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

Surmann‐Schmitt

Dietz

Kireva

et al. 2008

Journal of Biological Chemistry

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Here we report on the structure, expression, and function of a novel cartilage-specific gene coding for a 17-kDa small, highly charged, and secreted protein that we termed Ucma (unique cartilage matrix-associated protein). The protein is processed by a furin-like protease into an N-terminal peptide of 37 amino acids and a C-terminal fragment (Ucma-C) of 74 amino acids. Ucma is highly conserved between mouse, rat, human, dog, clawed frog, and zebrafish, but has no homology to other known proteins. Remarkable are 1-2 tyrosine sulfate residues/molecule and dense clusters of acidic and basic residues in the C-terminal part. In the developing mouse skeleton Ucma mRNA is expressed in resting chondrocytes in the distal and peripheral zones of epiphyseal and vertebral cartilage. Ucma is secreted into the extracellular matrix as an uncleaved precursor and shows the same restricted distribution pattern in cartilage as Ucma mRNA. In contrast, antibodies prepared against the processed C-terminal fragment located Ucma-C in the entire cartilage matrix, indicating that it either diffuses or is retained until chondrocytes reach hypertrophy. During differentiation of an MC615 chondrocyte subclone in vitro, Ucma expression parallels largely the expression of collagen II and decreases with maturation toward hypertrophic cells. Recombinant Ucma-C does not affect expression of chondrocyte-specific genes or proliferation of chondrocytes, but interferes with osteogenic differentiation of primary osteoblasts, mesenchymal stem cells, and MC3T3-E1 pre-osteoblasts. These findings suggest that Ucma may be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilage-bone interface.Elucidation of molecular mechanisms underlying chondrocyte differentiation is not only important for our understanding of skeletal development, but also of particular interest for our knowledge on the behavior of chondrocytes following articular cartilage damage during cartilage repair and treatment of degenerative cartilage diseases. Initial steps of chondrogenesis, i.e. the formation of a cartilage blastema from limb bud mesenchymal cells, include cell condensation and onset of chondrocyte differentiation marked by the expression of cartilage-specific matrix proteins such as aggrecan, collagen II, IX, and XI and others (1, 2). These events are regulated by the orchestrated action of several growth factors including BMPs, Wnt factors, FGFs, and the transcription factors Sox5,6, and 9 (3,4). Further steps of chondrocyte growth, maturation, and replacement by bone in the growth plate of long bones, ribs, and vertebrae during endochondral ossification can be defined by the stepwise onset or decline of differentially expressed genes: collagen II and Sox9 for resting and proliferating, FGFR3 for proliferating and prehypertrophic, Ihh and PTHrP receptor for prehypertrophic, collagen X for hypertrophic, and Runx2, osteocalcin, and MMP13 for late hypertrophic chondrocytes (...

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BMP signaling stimulates chondrocyte maturation and the expression of Indian hedgehog

Cited by 105 publications

References 37 publications

Hedgehog signaling enhances core-binding factor a1 and receptor activator of nuclear factor-kappaB ligand (RANKL) gene expression in chondrocytes

Hedgehog signaling enhances core-binding factor a1 and receptor activator of nuclear factor-kappaB ligand (RANKL) gene expression in chondrocytes

Indian hedgehog: Its roles and regulation in endochondral bone development

Ucma, a Novel Secreted Cartilage-specific Protein with Implications in Osteogenesis

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