Heterogeneity of colony stimulating factor-1 gene expression in the skeleton of four osteopetrotic mutations in rats and mice

Shalhoub, Victoria; Jackson, Mary E.; Paradise, Carol; Stein, Gary S.; Lian, Jane B.; Marks, Sandy C.

doi:10.1002/(sici)1097-4652(199602)166:2<340::aid-jcp12>3.0.co;2-f

Cited by 10 publications

(3 citation statements)

References 52 publications

(59 reference statements)

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“…Age-dependent changes of these mRNAs in wild-type mice were similar to previous studies reflecting osteoblast activity (Fig. 6) (4,19). In 2-day-old Runx2 neo7/neo7 mice, RT -PCR analyses were carried out for the mRNA levels of total Runx2 (Fig.…”

Section: Reduction Of Functional Runx2 Dosage Alters the Expression Of Osteoblast Marker Genes And Delays Cellular Differentiationsupporting

confidence: 84%

A Runx2 threshold for the cleidocranial dysplasia phenotype

Lou

Javed

Hussain

et al. 2008

Human Molecular Genetics

102

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Cleidocranial dysplasia (CCD) in humans is an autosomal-dominant skeletal disease that results from mutations in the bone-specific transcription factor RUNX2 (CBFA1/AML3). However, distinct RUNX2 mutations in CCD do not correlate with the severity of the disease. Here we generated a new mouse model with a hypomorphic Runx2 mutant allele (Runx2(neo7)), in which only part of the transcript is processed to full-length (wild-type) Runx2 mRNA. Homozygous Runx2(neo7/neo7) mice express a reduced level of wild-type Runx2 mRNA (55-70%) and protein. This mouse model allowed us to establish the minimal requirement of functional Runx2 for normal bone development. Runx2(neo7/neo7) mice have grossly normal skeletons with no abnormalities observed in the growth plate, but do exhibit developmental defects in calvaria and clavicles that persist through post-natal growth. Clavicle defects are caused by disrupted endochondral bone formation during embryogenesis. These hypomorphic mice have altered calvarial bone volume, as observed by histology and microCT imaging, and decreased expression of osteoblast marker genes. The bone phenotype of the heterozygous mice, which have 79-84% of wild-type Runx2 mRNA, is normal. These results show there is a critical gene dosage requirement of functional Runx2 for the formation of intramembranous bone tissues during embryogenesis. A decrease to 70% of wild-type Runx2 levels results in the CCD syndrome, whereas levels>79% produce a normal skeleton. Our findings suggest that the range of bone phenotypes in CCD patients is attributable to quantitative reduction in the functional activity of RUNX2.

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Section: Reduction Of Functional Runx2 Dosage Alters the Expression Of Osteoblast Marker Genes And Delays Cellular Differentiationsupporting

confidence: 84%

A Runx2 threshold for the cleidocranial dysplasia phenotype

Lou

Javed

Hussain

et al. 2008

Human Molecular Genetics

102

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“…Although the primary defect in osteopetrosis is recognized to be associated with failure in osteoclast differentiation and/or function, it has recently been suggested that osteoblast abnormalities may contribute to the pathogenesis of the disease. This aspect is likely to be associated with both alteration of bone matrix protein synthesis (31,32) or with the aberrant production of cytokines critical for normal osteoclast development and function, such as the CSF‐1 (33) …”

Section: Introductionmentioning

confidence: 99%

“…This aspect is likely to be associated with both alteration of bone matrix protein synthesis (31,32) or with the aberrant production of cytokines critical for normal osteoclast development and function, such as the CSF-1. (33) Despite substantial advances in the study of animal osteopetrosis, little is known yet on the cellular and molecular defects in the human syndrome. This is mostly due to both the rarity of the disease and genetic heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Osteoclast Dysfunction in Human Osteopetrosis: Abnormal Osteoclastogenesis and Lack of Osteoclast-Specific Adhesion Structures

Teti

Migliaccio

Taranta

et al. 1999

Journal of Bone and Mineral Research

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Osteoclasts from a patient affected by osteopetrosis were examined in vivo and in vitro. Iliac crest biopsy revealed an osteosclerotic pattern, with prominent numbers of osteoclasts noted for hypernuclearity and incomplete adherence to the bone surface. A population comprising tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated and mononuclear cells, and alkaline phosphatase-positive stromal fibroblasts was obtained in vitro from bone marrow. Mononuclear TRAP-positive precursors spontaneously fused in culture to form giant osteoclast-like cells. These cells expressed the osteoclast marker MMP-9 and calcitonin receptor, and lacked the macrophage marker, Fc receptor. Expression and distribution of c-src, c-fms, and CD68, and response to steroid hormones relevant to osteoclast differentiation and function were apparently normal, whereas cell retraction in response to calcitonin was impaired. TRAP-positive multinucleated cells did not form osteoclast-specific adhesion structures (clear zone, podosomes, or actin rings). Bone resorption rate was severely reduced in vitro. Focal adhesions and stress fibers were observed en lieu of podosomes and actin rings. Adhesion structures contained low levels of immunoreactive vitronectin receptor, most of this integrin being retained in cytoplasmic vesicles. These data provide the first characterization of abnormal differentiation and function of human osteopetrotic osteoclastlike

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Cloning the full-length cDNA for rat connective tissue growth factor: Implications for skeletal development

Smock

Safadi

et al. 2000

J. Cell. Biochem.

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The mammalian osteopetroses represent a pathogenetically diverse group of skeletal disorders characterized by excess bone mass resulting from reduced osteoclastic bone resorption. Abnormalities involving osteoblast function and skeletal development have also been reported in many forms of the disease. In this study, we used the rat mutation, osteopetrosis (op), to examine differences in skeletal gene expression between op mutants and their normal littermates. RNA isolated from calvaria and long bones was used as a template for mRNA-differential display. Sequence information for one of the many cDNA that were selectively expressed in either normal or mutant bone suggested that it is the rat homologue of connective tissue growth factor (CTGF) previously cloned in the human, mouse, and other species. A consensus sequence was assembled from overlapping 5'-RACE clones and used to confirm the rat CTGF cDNA protein coding region. Northern blot analysis confirmed that this message was highly (8- to 10-fold) over-expressed in op versus normal bone; it was also upregulated in op kidney but none of the other tissues (brain, liver, spleen, thymus) examined. In primary rat osteoblast cultures, the CTGF message exhibits a temporal pattern of expression dependent on their state of differentiation. Furthermore, CTGF expression is regulated by prostaglandin E(2), a factor known to modulate osteoblast differentiation. Since members of the CTGF family regulate the expression of specific genes, such as collagen and fibronectin, we propose that CTGF may play a previously unreported role in normal skeletal modeling/remodeling. Its dramatic over-expression in the op mutant skeleton may be secondary to the uncoupling of bone resorption and bone formation resulting in dysregulation of osteoblast gene expression and function.

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Heterogeneity of colony stimulating factor-1 gene expression in the skeleton of four osteopetrotic mutations in rats and mice

Cited by 10 publications

References 52 publications

A Runx2 threshold for the cleidocranial dysplasia phenotype

A Runx2 threshold for the cleidocranial dysplasia phenotype

Mechanisms of Osteoclast Dysfunction in Human Osteopetrosis: Abnormal Osteoclastogenesis and Lack of Osteoclast-Specific Adhesion Structures

Cloning the full-length cDNA for rat connective tissue growth factor: Implications for skeletal development

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