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Mx1-cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype.

ABSTRACT: Regulators of G-protein Signaling (Rgs) proteins are the members of a multigene family of GTPase-accelerating proteins (GAP) for the Galpha subunit of heterotrimeric G-proteins. Rgs proteins play critical roles in the regulation of G protein couple receptor (GPCR) signaling in normal physiology and human diseases such as cancer, heart diseases, and inflammation. Rgs12 is the largest protein of the Rgs protein family. Some in vitro studies have demonstrated that Rgs12 plays a critical role in regulating cell differentiation and migration; however its function and mechanism in vivo is largely unknown. Here, we generated a floxed Rgs12 allele (Rgs12(flox/flox) ) in which the exon 2, containing both PDZ and PTB_PID domains of Rgs12, was flanked with two loxp sites. By using the inducible Mx1-cre and Poly I:C system to specifically delete Rgs12 at postnatal 10 days in interferon-responsive cells including monocyte and macrophage cells, we found that Rgs12 mutant mice had growth retardation with the phenotype of increased bone mass. We further found that deletion of Rgs12 reduced osteoclast numbers and had no significant effect on osteoblast formation. Thus, Rgs12(flox/flox) conditional mice provide a valuable tool for in vivo analysis of Rgs12 function and mechanism through time- and cell-specific deletion of Rgs12.

SUBMITTER: Yang S

PROVIDER: S-EPMC3908791 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Mx1-cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype.

Yang Shuying S Li Yi-Ping YP Liu Tongjun T He Xiaoning X Yuan Xue X Li Chunyi C Cao Jay J Kim Yunjung Y

Genesis (New York, N.Y. : 2000) 20130225 3

Regulators of G-protein Signaling (Rgs) proteins are the members of a multigene family of GTPase-accelerating proteins (GAP) for the Galpha subunit of heterotrimeric G-proteins. Rgs proteins play critical roles in the regulation of G protein couple receptor (GPCR) signaling in normal physiology and human diseases such as cancer, heart diseases, and inflammation. Rgs12 is the largest protein of the Rgs protein family. Some in vitro studies have demonstrated that Rgs12 plays a critical role in reg ...[more]

PMID: 23349096

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Project description:Skeletal development and growth are complex processes regulated by multiple microenvironmental cues, including integrin-ECM interactions. The ?1 sub-family of integrins is the largest integrin sub-family and constitutes the main integrin binding partners of collagen I, the major ECM component of bone. As complete ?1 integrin knockout results in embryonic lethality, studies of ?1 integrin function in vivo rely on tissue-specific gene deletions. While multiple in vitro studies indicate that ?1 integrins are crucial regulators of osteogenesis and mineralization, in vivo osteoblast-specific perturbations of ?1 integrins have resulted in mild and sometimes contradictory skeletal phenotypes. To further investigate the role of ?1 integrins on skeletal phenotype, we used the Twist2-Cre, Osterix-Cre and osteocalcin-Cre lines to generate conditional ?1 integrin deletions, where Cre is expressed primarily in mesenchymal condensation, pre-osteoblast, and mature osteoblast lineage cells respectively within these lines. Mice with Twist2-specific ?1 integrin disruption were smaller, had impaired skeletal development, especially in the craniofacial and vertebral tissues at E19.5, and did not survive beyond birth. Osterix-specific ?1 integrin deficiency resulted in viable mice which were normal at birth but displayed early defects in calvarial ossification, incisor eruption and growth as well as femoral bone mineral density, structure, and mechanical properties. Although these defects persisted into adulthood, they became milder with age. Finally, a lack of ?1 integrins in mature osteoblasts and osteocytes resulted in minor alterations to femur structure but had no effect on mineral density, biomechanics or fracture healing. Taken together, our data indicate that ?1 integrin expression in early mesenchymal condensations play an important role in skeletal ossification, while ?1 integrin-ECM interactions in pre-osteoblast, odontoblast- and hypertrophic chondryocyte-lineage cells regulate incisor eruption and perinatal bone formation in both intramembranously and endochondrally formed bones in young, rapidly growing mice. In contrast, the osteocalcin-specific ?1 integrin deletion had only minor effects on skeletal phenotype.

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Mx1-cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype.

Publications

Mx1-cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype.

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