Identification of the Functional Domain of Osteoclast Inhibitory Peptide-1/hSca

Koide, Masanori; Kurihara, Noriyoshi; Maeda, Hidefumi; Reddy, Sakamuri V.

doi:10.1359/jbmr.2002.17.1.111

Cited by 10 publications

(18 citation statements)

References 37 publications

(73 reference statements)

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“…Non-adherent mononuclear cells from WT and SMA mouse bone marrow were cultured in methyl cellulose to form CFU-GM, as described previously [17]. Briefly, the non-adherent bone marrow cells (4 × 10 5 / ml) were cultured in Methocult H4230 (Stem Cell Technologies Inc., WA, USA) and incubated for 7 days.…”

Section: Methodsmentioning

confidence: 99%

Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy

Shanmugarajan¹,

Tsuruga²,

Swoboda

et al. 2009

The Journal of Pathology

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Spinal muscular atrophy (SMA) is characterized by degenerating lower motor neurons and an increased incidence of congenital bone fractures. Survival motor neuron (SMN) levels are significantly reduced due to deletions/mutations in the telomeric SMN1 gene in these patients. We utilized the Smn −/− SMN2 mouse model of SMA to determine the functional role for SMN in bone remodelling. μCT analysis of lumber vertebrae, tibia and femur bones from SMA mice revealed an osteoporotic bone phenotype. Histological analysis demonstrated a thin porous cortex of cortical bone and thin trabeculae at the proximal end of the growth plate in the vertebrae of SMA mice compared to wild-type mice. Histochemical staining of the vertebrae showed the presence of abundant activated osteoclasts on the sparse trabeculae and on the endosteal surface of the thin cortex in SMA mice. Histomorphometric analysis of vertebrae from SMA mice showed an increased number of osteoclasts. Serum TRAcP5b and urinary NTx levels were elevated, consistent with increased bone resorption in these mice. SMA mice showed a significant decrease in the levels of osteoblast differentiation markers, osteocalcin, osteopontin and osterix mRNA expression; however, there were no change in the levels of alkaline phosphatase expression compared to WT mice. SMA mouse bone marrow cultures revealed an increased rate of osteoclast formation (54%) and bone resorption capacity (46%) compared to WT mice. Pre-osteoclast cells from SMA mice showed constitutive upregulation of RANK receptor signalling molecules critical for osteoclast differentiation. Our results implicate SMN function in bone remodelling and skeletal pathogenesis in SMA. Understanding basic mechanisms of SMN action in bone remodelling may uncover new therapeutic targets for preventing bone loss/fracture risk in SMA.

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Section: Methodsmentioning

confidence: 99%

Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy

Shanmugarajan¹,

Tsuruga²,

Swoboda

et al. 2009

The Journal of Pathology

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“…OIP-1 shows 65% homology with mouse Sca-2. We have demonstrated that the OIP-1 c-peptide region is critical for its OCL inhibitory activity and that a neutralizing antibody against the c-peptide completely blocks OIP-1's capacity to inhibit OCL formation (Koide et al, 2002).…”

Section: Introductionmentioning

confidence: 92%

“…We have recently identified and characterized a novel inhibitor of osteoclast (OCL) formation termed OCL inhibitory peptide-1 (OIP-1/hSca) (Koide et al, 2002(Koide et al, , 2003. OIP-1/hSca is also termed, RIG-E (retinoic acid induced gene expression) or thymic shared antigen-1 (TSA-1) and is a Ly-6 gene family member expressed on immature thymocytes and thymic epithelial cells (Mao et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of human osteoclast inhibitory peptide-1 (OIP-1/hSca) gene promoter

Shanmugarajan

Ito

Kajiya

et al. 2006

Gene

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We have recently identified and characterized the human osteoclast (OCL) inhibitory peptide-1 (OIP-1/hSca), a member of Ly-6 gene family. OIP-1 is an important physiologic regulator of OCL development and bone resorption activity. To determine the molecular mechanisms that regulate OIP-1 gene expression in OCL precursor cells, we isolated and characterized the OIP-1/hSca gene (2 Kb) promoter sequence. IFN-γ (50 ng/ml) treatment of RAW 264.7 macrophage cells transfected with OIP-1 gene (−1 to −1988 bp relative to transcription start site) promoter-luciferase reporter plasmid demonstrated a significant (4 fold) increase in OIP-1 gene promoter activity. Sequence analysis of OIP-1 gene promoter region further identified a potential Stat-1 binding motif at −1629 to −1639 bp position. Stat-1 specific inhibitor, fludarabine (50 µM) abolished IFN-γ stimulated OIP-1 gene promoter activity. Electrophoretic mobility shift assay (EMSA) further confirmed activated Stat-1 binding to the OIP-1 gene promoter sequence suggesting that IFN-γ regulates OIP-1 gene expression in OCL precursor cells through a Stat-1 dependent signaling pathway. We further show that knock-down of TRADD enhances IFN-γ signaling to increase OIP-1 gene expression in OCL precursor cells. These results should provide insights into the molecular control of OIP-1 gene expression and inhibition of OCL activity in the bone microenvironment

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“…OIP-1/hSca is also known as retinoic acid induced gene expression (RIG-E) or thymic shared antigen-1 (TSA-1) and is a Ly-6 gene family member expressed on immature thymocytes and thymus epithelial cells. OIP-1/hSca is a glycophosphatidylinositol (GPI)-linked membrane protein (16 kDa) containing a 79 amino acid extracellular peptide and a 32 amino acid carboxy terminal GPI-linked peptide (c-peptide) [Koide et al, 2002]. OIP-1 has 65% homology with mouse Sca-2 at the nucleotide level.…”

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confidence: 99%

IL‐12 stimulates the osteoclast inhibitory peptide‐1 (OIP‐1/hSca) gene expression in CD4+ T cells

Shanmugarajan

Kawanabe

Koide

et al. 2009

J of Cellular Biochemistry

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Immune cell products such as interferon (IFN)-γ and interleukin (IL)-12 are potent inhibitors of osteoclast formation. We previously characterized the human osteoclast inhibitory peptide-1 (OIP-1/hSca), a Ly-6 gene family member and showed IFN-γ modulation of OIP-1 expression in bone marrow cells. Whether, IL-12 regulates OIP-1 expression in the bone microenvironment is unclear. Real-time PCR analysis revealed that IL-12 treatment significantly enhanced OIP-1 mRNA expression in human bone marrow mononuclear cells. Because IL-12 induces IFN-γ production by T cells, we tested whether IFN-γ participates in IL-12 stimulation of OIP-1 gene expression in these cells. IL-12 treatment in the presence of IFN-γ neutralizing antibody significantly increased OIP-1 mRNA expression, suggesting that IL-12 directly regulates OIP-1 gene expression. Interestingly, real-time PCR analysis demonstrated that IL-12 induces OIP-1 expression (3.2-fold) in CD4+ T cells; however, there was no significant change in CD8+ T cells. Also, IL-12 (10 ng/ml) treatment of Jurkat cells transfected with OIP-1 gene (−1 to −1,988 bp) promoter-luciferase reporter plasmid demonstrated a 5-fold and 2.7-fold increase in OIP-1 gene promoter activity in the presence and absence of antibody against IFN-γ, respectively. We showed that STAT-1,3 inhibitors treatment significantly decreased IL-12 stimulated OIP-1 promoter activity. Chromatin immunoprecipitation (ChIP) assay confirmed STAT-3, but not STAT-1 binding to the OIP-1 gene promoter in response to IL-12 stimulation. These results suggest that IL-12 stimulates the OIP-1 gene expression through STAT-3 activation in CD4+ T cells.

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Identification of the Functional Domain of Osteoclast Inhibitory Peptide-1/hSca

Cited by 10 publications

References 37 publications

Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy

Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy

Functional characterization of human osteoclast inhibitory peptide-1 (OIP-1/hSca) gene promoter

IL‐12 stimulates the osteoclast inhibitory peptide‐1 (OIP‐1/hSca) gene expression in CD4+ T cells

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Identification of the Functional Domain of Osteoclast Inhibitory Peptide-1/hSca

Cited by 10 publications

References 37 publications

Bone loss in survival motor neuron (Smn−/−SMN2) genetic mouse model of spinal muscular atrophy

Bone loss in survival motor neuron (Smn−/−SMN2) genetic mouse model of spinal muscular atrophy

Functional characterization of human osteoclast inhibitory peptide-1 (OIP-1/hSca) gene promoter

IL‐12 stimulates the osteoclast inhibitory peptide‐1 (OIP‐1/hSca) gene expression in CD4+ T cells

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Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy

Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy