Three recessive genes for congenital osteopetrosis in the Norway rat

Moutier, R; Toyama, Kyoko; Cotton, William R.; Gaines, James F.

doi:10.1093/oxfordjournals.jhered.a108705

Cited by 24 publications

(7 citation statements)

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“…Like toothless (tl) and incisors-absent (ia), op is an independent autosomal recessive mutation [Moutier et al, 1976] with characteristic phenotypic manifestations due to a failure of normal osteoclast function, i.e., a sclerotic skeleton generally lacking in marrow cavities. In op mu- Fig.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…3). In addition, these two mutations have proved to be resistant to cure by spleen cell transfers from normal littermates (Marks, 1977b;Marks, unpublished data;Moutier et al, 1976). These associations are puzzling and distinctive to these two osteopetrotic mutations.…”

Section: Discussionmentioning

confidence: 99%

Morphological evidence of reduced bone resorption in osteopetrotic (op) mice

Marks

1982

Am. J. Anat.

108

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Osteopetrosis, a metabolic bone disease in which a generalized accumulation of bone mass reduces or obliterates marrow cavities, is inherited as an autosomal recessive in several mammalian species. A recently discovered mutation in mice, the osteopetrosic (op) mutation, exhibits an elevation in bone matrix synthesis and a resistance to the hypercalcemic effects of exogenous parathyroid extract when young mutants are compared with normal littermates. This investigation examined the number, cytology, and ultrastructure of osteoclasts and the structure of bone surfaces in op mice in a morphologic assessment of bone resorption. Compared with normal littermates, op mice have a severe deficiency of osteoclasts, which also contain unusual toluidine blue-positive and electron-dense cytoplasmic inclusions and hypertrophy of clear zones and ruffled borders. Marrow spaces in op mice contained large numbers of megakaryocytes and large lipoid masses. Bone surfaces exhibiting evidence of resorption by scanning electron microscopy in normal littermates showed no evidence of resorption in op mice. Instead, these areas were characterized by morphologic features of bone formation. These data offer morphologic evidence of a reduction of bone resorption in this mutation. They are interpreted to mean 1) that op mice have a severe reduction in numbers or proliferative capacity of osteoclast precursors, which may be related to the cellular inclusions in the osteoclast population, and 2) that hypertrophy of the ruffled borders and clear zones of op osteoclasts is a compensatory attempt to increase bone resorption.

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“…Following CSF-1 and RANKL binding, precursor cells fuse and become multinucleated, attach to bone, differentiate, and become active, bone-resorbing cells. One naturally occurring osteopetrotic model is the toothless (tl/tl) rat, 5,6 an autosomal recessive mutation in which a frameshift in the CSF-1 gene causes severe osteopetrosis due a virtually complete lack of osteoclasts. 7,8 Injections of soluble, recombinant CSF-1 rapidly restore osteoclast populations and rescue many, but not all, aspects of the phenotype.…”

Section: Introductionmentioning

confidence: 99%

Chemokine and chemokine receptor expression during colony stimulating factor-1–induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1γ) in osteoclastogenesis in vivo and in vitro

Yang

Mailhot

MacKay

et al. 2006

Blood

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Osteoclasts differentiate from hematopoietic precursors under systemic and local controls. Chemokines and receptors direct leukocyte traffic throughout the body and may help regulate site-specific bone resorption. We investigated bone gene expression in vivo during rapid osteoclast differentiation induced by colonystimulating factor 1 (CSF-1) in Csf1-null toothless (tl/tl) rats. Long-bone RNA from CSF-1-treated tl/tl rats was analyzed by high-density microarray over a time course. TRAP (tartrate-resistant acid phosphatase)-positive osteoclasts appeared on day 2, peaked on day 4, and decreased slightly on day 6, as marrow space was expanding. TRAP and cathepsin K mRNA paralleled the cell counts. We examined all chemokine and receptor mRNAs on the arrays. CCL9 was strongly induced and peaked on day 2, as did its receptor, CCR1, and regulatory receptors c-Fms (CSF-1 receptor) and RANK (receptor activator of nuclear factor B).

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Three recessive genes for congenital osteopetrosis in the Norway rat

Cited by 24 publications

References 0 publications

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

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

Morphological evidence of reduced bone resorption in osteopetrotic (op) mice

Chemokine and chemokine receptor expression during colony stimulating factor-1–induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1γ) in osteoclastogenesis in vivo and in vitro

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