Expression and activity of Runx2 mediated by hyaluronan during chondrocyte differentiation

Tanne, Yuki; Tanimoto, Kotaro; Tanaka, Nobuaki; Ueki, M.; Lin, Yu-Yu; Ohkuma, Satoru; Kamiya, Takashi; Tanaka, Eiji; Tanne, Kazuo

doi:10.1016/j.archoralbio.2007.12.007

Cited by 14 publications

(13 citation statements)

References 37 publications

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“…Alternatively, we suggest that the interaction of pericellular HA with CD44 in hypertrophying chondrocytes might modulate or augment some of the signaling networks that regulate the progression of chondrocyte maturation. Significantly, in the chondrocytic cell line ATDC5, expression of Has2 and Runx2, a crucial transcriptional regulator of chondrocyte maturation, is concomitantly upregulated at the onset of hypertrophic maturation (Tanne et al, 2008). Moreover, disruption of HA-CD44 interactions by addition of HA oligosaccharides or anti-CD44 antibodies inhibits Runx2 expression, as well as the expression of hypertrophic markers including type X collagen (Tanne et al, 2008).…”

Section: Development Developmentmentioning

confidence: 99%

“…Significantly, in the chondrocytic cell line ATDC5, expression of Has2 and Runx2, a crucial transcriptional regulator of chondrocyte maturation, is concomitantly upregulated at the onset of hypertrophic maturation (Tanne et al, 2008). Moreover, disruption of HA-CD44 interactions by addition of HA oligosaccharides or anti-CD44 antibodies inhibits Runx2 expression, as well as the expression of hypertrophic markers including type X collagen (Tanne et al, 2008). These results further indicate that HA-CD44 interactions might indeed play an important role in regulating chondrocyte maturation.…”

Section: Development Developmentmentioning

confidence: 99%

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Conditional inactivation ofHas2reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb

et al. 2009

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The glycosaminoglycan hyaluronan (HA) is a structural component of extracellular matrices and also interacts with cell surface receptors to directly influence cell behavior. To explore functions of HA in limb skeletal development, we conditionally inactivated the gene for HA synthase 2, Has2, in limb bud mesoderm using mice that harbor a floxed allele of Has2 and mice carrying a limb mesoderm-specific Prx1-Cre transgene. The skeletal elements of Has2-deficient limbs are severely shortened, indicating that HA is essential for normal longitudinal growth of all limb skeletal elements. Proximal phalanges are duplicated in Has2 mutant limbs indicating an involvement of HA in patterning specific portions of the digits. The growth plates of Has2-deficient skeletal elements are severely abnormal and disorganized, with a decrease in the deposition of aggrecan in the matrix and a disruption in normal columnar cellular relationships. Furthermore, there is a striking reduction in the number of hypertrophic chondrocytes and in the expression domains of markers of hypertrophic differentiation in the mutant growth plates, indicating that HA is necessary for the normal progression of chondrocyte maturation. In addition, secondary ossification centers do not form in the central regions of Has2 mutant growth plates owing to a failure of hypertrophic differentiation. In addition to skeletal defects, the formation of synovial joint cavities is defective in Has2-deficient limbs. Taken together, our results demonstrate that HA has a crucial role in skeletal growth, patterning, chondrocyte maturation and synovial joint formation in the developing limb.

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Section: Development Developmentmentioning

confidence: 99%

Section: Development Developmentmentioning

confidence: 99%

Conditional inactivation ofHas2reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb

et al. 2009

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“…Altered levels of CD44 have been seen in many epithelial neoplasms and expression of CD44 has been shown to carry prognostic implications [35,36]. RUNX2 expression is regulated by CD44 signaling [37]. A neutralizing antibody to CD44s significantly decreased the expression of Runx2 mRNA in hypertrophic chondrocytes [37].…”

Section: Introductionmentioning

confidence: 99%

Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis

2012

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BackgroundBone loss and pathological fractures are common skeletal complications associated with androgen deprivation therapy and bone metastases in prostate cancer patients. We have previously demonstrated that prostate cancer cells secrete receptor activator of NF-kB ligand (RANKL), a protein essential for osteoclast differentiation and activation. However, the mechanism(s) by which RANKL is produced remains to be determined. The objective of this study is to gain insight into the molecular mechanisms controlling RANKL expression in metastatic prostate cancer cells.ResultsWe show here that phosphorylation of Smad 5 by integrin αvβ3 and RUNX2 by CD44 signaling, respectively, regulates RANKL expression in human-derived PC3 prostate cancer cells isolated from bone metastasis. We found that RUNX2 intranuclear targeting is mediated by phosphorylation of Smad 5. Indeed, Smad5 knock-down via RNA interference and inhibition of Smad 5 phosphorylation by an αv inhibitor reduced RUNX2 nuclear localization and RANKL expression. Similarly, knockdown of CD44 or RUNX2 attenuated the expression of RANKL. As a result, conditioned media from these cells failed to support osteoclast differentiation in vitro. Immunohistochemistry analysis of tissue microarray sections containing primary prostatic tumor (grade2-4) detected predominant localization of RUNX2 and phosphorylated Smad 5 in the nuclei. Immunoblotting analyses of nuclear lysates from prostate tumor tissue corroborate these observations.ConclusionsCollectively, we show that CD44 signaling regulates phosphorylation of RUNX2. Localization of RUNX2 in the nucleus requires phosphorylation of Smad-5 by integrin αvβ3 signaling. Our results suggest possible integration of two different pathways in the expression of RANKL. These observations imply a novel mechanistic insight into the role of these proteins in bone loss associated with bone metastases in patients with prostate cancer.

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“…(25,(28)(29)(30) Recently, multiple biologic functions of Runx2 have been demonstrated in various cell types, including chondrocytes, endothelial cells, osteosarcoma cells, T-cell lymphomas, and breast cancer cells. (31)(32)(33)(34)(35) One of the central players in the osteoblast differentiation process is the Runx2 transcription factor, which coordinates multiple signals involved in osteoblast differentiation. Up to the present, several regulators such as Stat1, Twist, Hey1, and Notch1 have been shown to form inhibitory complexes with Runx2 and to inhibit osteoblast differentiation.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

Ann

Kim

Choi

et al. 2010

Journal of Bone and Mineral Research

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Notch1 genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch1 signaling in osteogenesis is not well defined. Notch1 controls osteoblast differentiation by affecting Runx2, but the question arises whether normal osteoblastic differentiation can occur regardless of the presence of Notch1. In this study, we observed the downregulation of Notch1 signaling during osteoblastic differentiation. BMPR‐IB/Alk6‐induced Runx2 proteins reduced Notch1 activity to a marked degree. Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1‐IC‐RBP‐Jk complex. Using deletion mutants, we also determined that the N‐terminal domain of Runx2 was crucial to the binding and inhibition of the N‐terminus of the Notch1 intracellular domain. Notably, upregulation of the Runx2 protein level paralleled reduced expression of Hes1, which is a downstream target of Notch1, during osteoblast differentiation. Collectively, our data suggest that Runx2 is an inhibitor of the Notch1 signaling pathway during normal osteoblast differentiation. © 2011 American Society for Bone and Mineral Research.

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Expression and activity of Runx2 mediated by hyaluronan during chondrocyte differentiation

Cited by 14 publications

References 37 publications

Conditional inactivation ofHas2reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb

Conditional inactivation ofHas2reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb

Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

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