Mice lacking smooth muscle calponin display increased bone formation that is associated with enhancement of bone morphogenetic protein responses

Yoshikawa, Hideki; Taniguchi, Shun’ichiro; Yamamura, Hisako; Mori, Shigeki; Sugimoto, Masamichi; Miyado, Kenji; Nakamura, Kenji; Nakao, Kazuki; Katsuki, Motoya; Shibata, Nobuhiko; Takahashi, Katsuhito

doi:10.1046/j.1365-2443.1998.00214.x

Cited by 60 publications

(87 citation statements)

References 52 publications

(40 reference statements)

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“…It is interesting to contrast the findings reported here with several other smooth muscle-restricted actin-binding proteins that are dispensable for similar functional activity in these organs, including CNN1 (17,36), TAGLN (37), CSRP1 (38), and CALD1 (39), which would suggest that compensatory pathways exist to preserve normal organ function in the absence of each of these actin-binding proteins. On the other hand, genetic inactivation of Myh11, encoding the major thick filament protein in smooth muscle, leads to megacystis, a decrease in intestinal motility, defective contraction of the bladder, and early postnatal death, all of which are reminiscent of the Lmod1 −/− phenotype and human MMIHS (40).…”

Section: Discussioncontrasting

confidence: 55%

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Halim

Wilson

Oliver

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

108

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Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal–contractile coupling.

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Section: Discussioncontrasting

confidence: 55%

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Halim

Wilson

Oliver

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

108

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“…Twenty to thirty primary cultures of murine calvarial cells were obtained from the twenty to thirty neonatal ICR mice 1 day after birth by sequential collagenase/trypsin digestion [34]. The mouse bone marrow-derived stromal cell line ST2 (RCB0224) was obtained from the Riken Cell Bank (Tsukuba, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…Cultured for 16 days, cells were fixed for 30 minutes with 3.7% formaldehyde/PBS at RT. After washing with PBS, nodules were stained with 1% alizarin red S (Sigma) at pH 6.0 [34].…”

Section: Methodsmentioning

confidence: 99%

“…With this model we can reproducibly induce ectopic bone and assess bone formation quantitatively in any wildtype or transgenic mice [17,34]. Our studies suggest granulocyte colony-stimulating factor (G-CSF) [17], basic calponin [34], and TNP-470 [22] (a synthetic anti-angiogenic agent) inhibit BMP-induced bone formation. Using this in vivo system, it should be possible to search for stimulators of BMP-induced bone formation.…”

Section: Introductionmentioning

confidence: 92%

“…To explore the mechanism for BMP-induced bone formation, we developed an in vivo experimental model system for the local delivery of recombinant human BMP-2 (rhBMP-2) impregnated in pepsin-digested Type I collagen [29]. With this model we can reproducibly induce ectopic bone and assess bone formation quantitatively in any wildtype or transgenic mice [17,34]. Our studies suggest granulocyte colony-stimulating factor (G-CSF) [17], basic calponin [34], and TNP-470 [22] (a synthetic anti-angiogenic agent) inhibit BMP-induced bone formation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

Yoshikawa

Yoshioka

Nakase

et al. 2009

Clin Orthop Relat Res

Self Cite

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The small GTPase Rho and Rho-associated protein kinase (Rho kinase, ROCK) signal participates in a variety of biological functions including vascular contraction, tumor invasion, and penile erection. Evidence also suggests Rho-ROCK is involved in signaling for mesenchymal cellular differentiation. However, whether it is involved in osteoblastic differentiation is unknown. We therefore asked whether Rho-ROCK signaling participates in recombinant human bone morphogenetic protein (rhBMP-2)-induced osteogenesis both in vitro and in vivo. Continuous delivery of a specific ROCK inhibitor (Y-27632) enhanced ectopic bone formation induced by rhBMP-2 impregnated into an atelocollagen carrier in mice without affecting systemic bone metabolism. Treatment with Y-27632 also enhanced the osteoblastic differentiation of cultured murine neonatal calvarial cells. These effects were associated with increased expression of BMP-4 gene. Expression of a dominant negative mutant of ROCK in ST2 cells promoted osteoblastic differentiation, while a constitutively active mutant of ROCK attenuated osteoblastic differentiation and the ROCK inhibitor reversed this phenotype. Thus, ROCK inhibits osteogenesis, and a ROCK inhibitor in combination with the local delivery of rhBMP/collagen composite may be clinically applicable for stimulating bone formation.

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Calponin

Thorneloe

Walsh

2002

Wiley Encyclopedia of Molecular Medicine

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Mice lacking smooth muscle calponin display increased bone formation that is associated with enhancement of bone morphogenetic protein responses

Cited by 60 publications

References 52 publications

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

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