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Article: Measles virus nucleocapsid protein modulates the Signal Regulatory Protein-β1 (SIRPβ1) to enhance osteoclast differentiation in Paget's disease of bone.

Sundaram, Kumaran / Sambandam, Yuvaraj / Shanmugarajan, Srinivasan / Rao, D Sudhaker / Reddy, Sakamuri V

2016 Volume 7, Page(s) 26–32

Abstract: Paget's disease of bone (PDB) is a chronic localized bone disorder in an elderly population. Environmental factors such as paramyxovirus are implicated in PDB and measles virus nucleocapsid protein (MVNP) has been shown to induce pagetic osteoclasts ( ... ...

Abstract	Paget's disease of bone (PDB) is a chronic localized bone disorder in an elderly population. Environmental factors such as paramyxovirus are implicated in PDB and measles virus nucleocapsid protein (MVNP) has been shown to induce pagetic osteoclasts (OCLs). However, the molecular mechanisms underlying MVNP stimulation of OCL differentiation in the PDB are unclear. We therefore determined the MVNP regulated gene expression profiling during OCL differentiation. Agilent microarray analysis of gene expression identified high levels of SIRPβ1 (353-fold) expression in MVNP transduced human bone marrow mononuclear cells stimulated with RANKL. Real-time PCR analysis further confirmed that MVNP alone upregulates SIRPβ1 mRNA expression in these cells. Also, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. We further show that MVNP increases SIRPβ1 interaction with DAP12 adaptor protein in the presence and absence of RANKL stimulation. shRNA knockdown of SIRPβ1 expression in normal human bone marrow monocytes decreased the levels of MVNP enhanced p-Syk and c-Fos expression. In addition, SIRPβ1 knockdown significantly decreased MVNP stimulated dendritic cell-specific transmembrane protein (DC-STAMP) and connective tissue growth factor (CTGF) mRNA expression during OCL differentiation. Furthermore, we demonstrated the contribution of SIRPβ1 in MVNP induced OCL formation and bone resorption. Thus, our results suggest that MVNP modulation of SIRPβ1 provides new insights into the molecular mechanisms which control high bone turnover in PDB.
Language	English
Publishing date	2016-06-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2821774-3
ISSN	2352-1872
ISSN	2352-1872
DOI	10.1016/j.bonr.2016.06.002
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Article ; Online: Combined Effects of Simulated Microgravity and Radiation Exposure on Osteoclast Cell Fusion.

Shanmugarajan, Srinivasan / Zhang, Ye / Moreno-Villanueva, Maria / Clanton, Ryan / Rohde, Larry H / Ramesh, Govindarajan T / Sibonga, Jean D / Wu, Honglu

International journal of molecular sciences

2017 Volume 18, Issue 11

Abstract: The loss of bone mass and alteration in bone physiology during space flight are one of the major health risks for astronauts. Although the lack of weight bearing in microgravity is considered a risk factor for bone loss and possible osteoporosis, ... ...

Abstract	The loss of bone mass and alteration in bone physiology during space flight are one of the major health risks for astronauts. Although the lack of weight bearing in microgravity is considered a risk factor for bone loss and possible osteoporosis, organisms living in space are also exposed to cosmic radiation and other environmental stress factors. As such, it is still unclear as to whether and by how much radiation exposure contributes to bone loss during space travel, and whether the effects of microgravity and radiation exposure are additive or synergistic. Bone is continuously renewed through the resorption of old bone by osteoclast cells and the formation of new bone by osteoblast cells. In this study, we investigated the combined effects of microgravity and radiation by evaluating the maturation of a hematopoietic cell line to mature osteoclasts. RAW 264.7 monocyte/macrophage cells were cultured in rotating wall vessels that simulate microgravity on the ground. Cells under static 1g or simulated microgravity were exposed to γ rays of varying doses, and then cultured in receptor activator of nuclear factor-κB ligand (RANKL) for the formation of osteoclast giant multinucleated cells (GMCs) and for gene expression analysis. Results of the study showed that radiation alone at doses as low as 0.1 Gy may stimulate osteoclast cell fusion as assessed by GMCs and the expression of signature genes such as tartrate resistant acid phosphatase (
MeSH term(s)	Animals ; Cell Culture Techniques ; Cell Fusion ; Cell Proliferation/radiation effects ; Gene Expression Regulation/radiation effects ; Macrophages/cytology ; Macrophages/metabolism ; Macrophages/radiation effects ; Membrane Proteins/metabolism ; Mice ; Osteoclasts/cytology ; Osteoclasts/metabolism ; Osteoclasts/radiation effects ; RANK Ligand/pharmacology ; RAW 264.7 Cells ; Tartrate-Resistant Acid Phosphatase/metabolism ; Weightlessness/adverse effects
Chemical Substances	Membrane Proteins ; RANK Ligand ; Acp5 protein, mouse (EC 3.1.3.2) ; Tartrate-Resistant Acid Phosphatase (EC 3.1.3.2)
Language	English
Publishing date	2017-11-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms18112443
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Article ; Online: Osteoclast inhibitory peptide-1 binding to the Fc gammaRIIB inhibits osteoclast differentiation.

Shanmugarajan, Srinivasan / Beeson, Craig C / Reddy, Sakamuri V

Endocrinology

2010 Volume 151, Issue 9, Page(s) 4389–4399

Abstract: Osteoclast inhibitory peptide-1 (OIP) is an autocrine/paracrine inhibitor of osteoclast differentiation, and mice that overexpress OIP-1 in osteoclast lineage cells develop an osteopetrosis bone phenotype. In this study, we show that OIP-1 binding to the ...

Abstract	Osteoclast inhibitory peptide-1 (OIP) is an autocrine/paracrine inhibitor of osteoclast differentiation, and mice that overexpress OIP-1 in osteoclast lineage cells develop an osteopetrosis bone phenotype. In this study, we show that OIP-1 binding to the Fc gamma receptor IIB (Fc gammaRIIB) inhibits osteoclast differentiation. Confocal microscopy revealed colocalization of OIP-1 with Fc gammaRIIB in osteoclasts, and we observed that OIP-1 carboxy-terminal GPI-linked peptide forms a 1:1 complex with recombinant Fc gammaRIIB protein with an affinity binding of a dissociation constant of approximately 4 microm. Immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter proteins (FcR gamma and DNAX-activating protein of molecular mass 12 kDa) are critical for osteoclast development, and OIP-1 transgenic mouse-derived preosteoclast cells demonstrated suppression (6-fold) of ITAM phosphorylation of FcR gamma but not DNAX-activating protein of molecular mass 12 kDa. Interestingly, these preosteoclast cells demonstrated increased levels (4-fold) of immunoreceptor tyrosine-based inhibitory motif phosphorylation of Fc gammaRIIB and Src homology 2-domain-containing proteins tyrosine phosphatase 1 activation. Further, OIP-1 mouse-derived preosteoclasts cells demonstrated inhibition of spleen tyrosine kinase activation (4.5-fold), compared with wild-type mice. These results suggest that cross-regulation of immunoreceptor tyrosine-based inhibitory motif and ITAM bearing Fc receptors may play a role in OIP-1 suppression of spleen tyrosine kinase activation and inhibition of osteoclast differentiation. Thus, OIP-1 is an important physiologic regulator of osteoclast development and may have therapeutic utility for bone diseases with high bone turnover.
MeSH term(s)	ATPases Associated with Diverse Cellular Activities ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Sequence ; Animals ; Blotting, Western ; Cell Differentiation ; Cell Line ; Intracellular Signaling Peptides and Proteins/metabolism ; LIM Domain Proteins ; Mice ; Mice, Knockout ; Mice, Transgenic ; Microscopy, Confocal ; Molecular Sequence Data ; Osteoclasts/cytology ; Osteoclasts/metabolism ; Phosphorylation ; Proteasome Endopeptidase Complex ; Protein Binding ; Protein-Tyrosine Kinases/metabolism ; RNA Interference ; Receptors, IgG/genetics ; Receptors, IgG/metabolism ; Syk Kinase ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transfection
Chemical Substances	Adaptor Proteins, Signal Transducing ; Fc gamma receptor IIB ; Intracellular Signaling Peptides and Proteins ; LIM Domain Proteins ; PSMC5 protein, human ; Receptors, IgG ; Transcription Factors ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Syk Kinase (EC 2.7.10.2) ; Syk protein, mouse (EC 2.7.10.2) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-)
Language	English
Publishing date	2010-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2010-0244
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Article ; Online: NIP45 negatively regulates RANK ligand induced osteoclast differentiation.

Shanmugarajan, Srinivasan / Haycraft, Courtney J / Reddy, Sakamuri V / Ries, William L

Journal of cellular biochemistry

2011 Volume 113, Issue 4, Page(s) 1274–1281

Abstract: Receptor activator of NF-κB ligand (RANKL)-RANK receptor signaling to induce NFATc1 transcription factor is critical for osteoclast differentiation and bone resorption. RANK adaptor proteins, tumor necrosis factor receptor-associated factors (TRAFs) play ...

Abstract	Receptor activator of NF-κB ligand (RANKL)-RANK receptor signaling to induce NFATc1 transcription factor is critical for osteoclast differentiation and bone resorption. RANK adaptor proteins, tumor necrosis factor receptor-associated factors (TRAFs) play an essential role in RANKL signaling. Evidence indicates that NIP45 (NFAT interacting protein) binds with TRAFs and NFATc2. We therefore hypothesized that NIP45 regulates RANKL induced osteoclast differentiation. In this study, we demonstrate that RANKL treatment down regulates NIP45 expression in mouse bone marrow derived pre-osteoclast cells. Lentiviral (pGIPZ) mediated shRNA knock-down of NIP45 expression in RANKL stimulated pre-osteoclast cells resulted in increased levels of NFATc1, NFATc2, and TRAF6 but not TRAF2 expression compared to control shRNA transduced cells. Also, NIP45 suppression elevated p-IκB-α levels and NF-κB-luciferase reporter activity. Confocal microscopy demonstrated NIP45 colocalized with TRAF6 in the cytosol of osteoclast progenitor cells. In contrast, RANKL stimulation induced NIP45 nuclear translocation and colocalization with NFATc2 in these cells. Coimmuneprecipitation assay demonstrated NIP45 binding with NFATc2 but not NFATc1. We further show that shRNA knock-down of NIP45 expression in pre-osteoclast cells significantly increased RANKL induced osteoclast differentiation and bone resorption activity. Taken together, our results indicate that RANKL signaling down regulates NIP45 expression and that NIP45 is a negative regulator of osteoclast differentiation.
MeSH term(s)	Animals ; Blotting, Western ; Cell Differentiation/physiology ; Cells, Cultured ; Down-Regulation ; Immunoprecipitation ; Intracellular Signaling Peptides and Proteins/physiology ; Mice ; Microscopy, Confocal ; NFATC Transcription Factors/metabolism ; Nuclear Proteins/physiology ; Osteoclasts/cytology ; RANK Ligand/physiology ; Signal Transduction/physiology ; TNF Receptor-Associated Factor 6/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; NFATC Transcription Factors ; Nfatc2 protein, mouse ; Nfatc2ip protein, mouse ; Nuclear Proteins ; RANK Ligand ; TNF Receptor-Associated Factor 6 ; Tnfsf11 protein, mouse
Language	English
Publishing date	2011-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.23460
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Article ; Online: Mutant p62P392L stimulation of osteoclast differentiation in Paget's disease of bone.

Sundaram, Kumaran / Shanmugarajan, Srinivasan / Rao, D Sudhaker / Reddy, Sakamuri V

Endocrinology

2011 Volume 152, Issue 11, Page(s) 4180–4189

Abstract: Paget's disease of the bone (PDB) is an autosomal dominant trait with genetic heterogeneity, characterized by abnormal osteoclastogenesis. Sequestosome 1 (p62) is a scaffold protein that plays an important role in receptor activator of nuclear factor κB ( ...

Abstract	Paget's disease of the bone (PDB) is an autosomal dominant trait with genetic heterogeneity, characterized by abnormal osteoclastogenesis. Sequestosome 1 (p62) is a scaffold protein that plays an important role in receptor activator of nuclear factor κB (RANK) signaling essential for osteoclast (OCL) differentiation. p62P392L mutation in the ubiquitin-associated (UBA) domain is widely associated with PDB; however, the mechanisms by which p62P392L stimulate OCL differentiation in PDB are not completely understood. Deubiquitinating enzyme cylindromatosis (CYLD) has been shown to negatively regulate RANK ligand-RANK signaling essential for OCL differentiation. Here, we report that CYLD binds with the p62 wild-type (p62WT), non-UBA mutant (p62A381V) but not with the UBA mutant (p62P392L) in OCL progenitor cells. Also, p62P392L induces expression of c-Fos (2.8-fold) and nuclear factor of activated T cells c1 (6.0-fold) transcription factors critical for OCL differentiation. Furthermore, p62P392L expression results in accumulation of polyubiquitinated TNF receptor-associated factor (TRAF)6 and elevated levels of phospho-IκB during OCL differentiation. Retroviral transduction of p62P392L/CYLD short hairpin RNA significantly increased TRAP positive multinucleated OCL formation/bone resorption activity in mouse bone marrow cultures. Thus, the p62P392L mutation abolished CYLD interaction and enhanced OCL development/bone resorption activity in PDB.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Bone Resorption/genetics ; Bone Resorption/metabolism ; Cell Differentiation/drug effects ; Cell Differentiation/physiology ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Mice ; Mutation ; Osteitis Deformans/genetics ; Osteitis Deformans/metabolism ; Osteoclasts/physiology ; RANK Ligand/metabolism ; Receptor Activator of Nuclear Factor-kappa B/metabolism ; Sequestosome-1 Protein ; Signal Transduction/drug effects ; Signal Transduction/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Heat-Shock Proteins ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; Sequestosome-1 Protein ; Sqstm1 protein, mouse
Language	English
Publishing date	2011-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2011-1225
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Article ; Online: Combined Effects of Simulated Microgravity and Radiation Exposure on Osteoclast Cell Fusion

Srinivasan Shanmugarajan / Ye Zhang / Maria Moreno-Villanueva / Ryan Clanton / Larry H. Rohde / Govindarajan T. Ramesh / Jean D. Sibonga / Honglu Wu

International Journal of Molecular Sciences, Vol 18, Iss 11, p

2017 Volume 2443

Abstract	The loss of bone mass and alteration in bone physiology during space flight are one of the major health risks for astronauts. Although the lack of weight bearing in microgravity is considered a risk factor for bone loss and possible osteoporosis, organisms living in space are also exposed to cosmic radiation and other environmental stress factors. As such, it is still unclear as to whether and by how much radiation exposure contributes to bone loss during space travel, and whether the effects of microgravity and radiation exposure are additive or synergistic. Bone is continuously renewed through the resorption of old bone by osteoclast cells and the formation of new bone by osteoblast cells. In this study, we investigated the combined effects of microgravity and radiation by evaluating the maturation of a hematopoietic cell line to mature osteoclasts. RAW 264.7 monocyte/macrophage cells were cultured in rotating wall vessels that simulate microgravity on the ground. Cells under static 1g or simulated microgravity were exposed to γ rays of varying doses, and then cultured in receptor activator of nuclear factor-κB ligand (RANKL) for the formation of osteoclast giant multinucleated cells (GMCs) and for gene expression analysis. Results of the study showed that radiation alone at doses as low as 0.1 Gy may stimulate osteoclast cell fusion as assessed by GMCs and the expression of signature genes such as tartrate resistant acid phosphatase (Trap) and dendritic cell-specific transmembrane protein (Dcstamp). However, osteoclast cell fusion decreased for doses greater than 0.5 Gy. In comparison to radiation exposure, simulated microgravity induced higher levels of cell fusion, and the effects of these two environmental factors appeared additive. Interestingly, the microgravity effect on osteoclast stimulatory transmembrane protein (Ocstamp) and Dcstamp expressions was significantly higher than the radiation effect, suggesting that radiation may not increase the synthesis of adhesion molecules as much as microgravity.
Keywords	microgravity ; radiation ; osteoclast ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease.

Contreras, Miguel Agustin / Ries, William Louis / Shanmugarajan, Srinivasan / Arboleda, Gonzalo / Singh, Inderjit / Singh, Avtar Kaur

Biochimica et biophysica acta

2010 Volume 1802, Issue 7-8, Page(s) 601–608

Abstract: Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal ... ...

Abstract	Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, twi), we studied their femora. This study reports that twi femora are smaller than of those of wild type (wt), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult twi animals as compared to wt, without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in twi animals when compared to wt. To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from twi as compared to wt littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in twi mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration.
MeSH term(s)	Animals ; Animals, Newborn ; Bone Development/physiology ; Bone Diseases, Developmental/etiology ; Bone Diseases, Developmental/metabolism ; Bone Diseases, Developmental/pathology ; Bone Diseases, Developmental/physiopathology ; Bone Remodeling/physiology ; Cytokines/metabolism ; Disease Models, Animal ; Insulin-Like Growth Factor I/analysis ; Insulin-Like Growth Factor I/metabolism ; Leukodystrophy, Globoid Cell/complications ; Leukodystrophy, Globoid Cell/metabolism ; Leukodystrophy, Globoid Cell/pathology ; Leukodystrophy, Globoid Cell/physiopathology ; Liver/metabolism ; Liver/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Psychosine/metabolism ; Risk Factors
Chemical Substances	Cytokines ; Psychosine (2238-90-6) ; Insulin-Like Growth Factor I (67763-96-6)
Language	English
Publishing date	2010-05-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2010.04.006
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Article ; Online: Bone loss in survival motor neuron (Smn(-/-) SMN2) genetic mouse model of spinal muscular atrophy.

Shanmugarajan, Srinivasan / Tsuruga, Eichi / Swoboda, Kathryn J / Maria, Bernard L / Ries, William L / Reddy, Sakamuri V

The Journal of pathology

2009 Volume 219, Issue 1, Page(s) 52–60

Abstract: 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 ...

Abstract	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. microCT 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 up-regulation 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.
MeSH term(s)	Animals ; Biomarkers/analysis ; Bone Density ; Bone Remodeling ; Cells, Cultured ; Gene Expression ; Imaging, Three-Dimensional ; Mice ; Mice, Knockout ; Models, Animal ; Muscular Atrophy, Spinal/genetics ; Muscular Atrophy, Spinal/pathology ; Osteoclasts/metabolism ; Osteoclasts/pathology ; Receptor Activator of Nuclear Factor-kappa B/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Signal Transduction/physiology ; Survival of Motor Neuron 2 Protein/genetics ; Tibia/diagnostic imaging ; Tibia/metabolism ; Tibia/pathology ; Tomography, X-Ray Computed
Chemical Substances	Biomarkers ; Receptor Activator of Nuclear Factor-kappa B ; Survival of Motor Neuron 2 Protein ; Tnfrsf11a protein, mouse
Language	English
Publishing date	2009-05-11
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.2566
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Article ; Online: Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity.

Shanmugarajan, Srinivasan / Youssef, Rimon F / Pati, Parmita / Ries, William L / Rao, D Sudhaker / Reddy, Sakamuri V

Journal of cellular biochemistry

2008 Volume 104, Issue 4, Page(s) 1500–1508

Abstract: Paget's disease (PD) of bone is characterized by increased activity of large abnormal osteoclasts (OCLs) which contain paramyxoviral nuclear and cytoplasmic inclusions. MVNP gene expression has been shown to induce pagetic phenotype in OCLs. We ... ...

Abstract	Paget's disease (PD) of bone is characterized by increased activity of large abnormal osteoclasts (OCLs) which contain paramyxoviral nuclear and cytoplasmic inclusions. MVNP gene expression has been shown to induce pagetic phenotype in OCLs. We previously characterized the osteoclast inhibitory peptide-1 (OIP-1/hSca) which inhibits OCL formation/bone resorption. OIP-1 is a glycophosphatidylinositol (GPI)-linked membrane protein containing a 79 amino acid extra cellular peptide and a 32 amino acid carboxy terminal GPI-linked peptide (c-peptide) which is critical for OCL inhibition. In this study, we demonstrate that OIP-1 c-peptide significantly decreased (43%) osteoclast differentiation of peripheral blood mononuclear cells from patients with PD. Also, OIP-1 treatment to normal human bone marrow mononuclear cells transduced with the MVNP inhibited (41%) osteoclast precursor (CFU-GM) growth in methyl-cellulose cultures. We further tested if OIP-1 overexpression in the OCL lineage in transgenic mice inhibits MVNP stimulated OCL formation. MVNP transduction and RANKL stimulation of OIP-1 mouse bone marrow cells showed a significant decrease (43%) in OCL formation and inhibition (38%) of bone resorption area compared to wild-type mice. Western blot analysis identified that OIP-1 decreased (3.5-fold) MVNP induced TRAF2 expression during OCL differentiation. MVNP or OIP-1 expression did not affect TRAF6 levels. Furthermore, OIP-1 expression resulted in a significant inhibition of MVNP stimulated ASK1, Rac1, c-Fos, p-JNK, and NFATc1 expression during OCL differentiation. These results suggest that OIP-1 inhibits MVNP induced pagetic OCL formation/activity through suppression of RANK signaling. Thus, OIP-1 may have therapeutic utility against excess bone resorption in patients with PD.
MeSH term(s)	ATPases Associated with Diverse Cellular Activities ; Adaptor Proteins, Signal Transducing/pharmacology ; Animals ; Bone Resorption/drug therapy ; Cell Differentiation/drug effects ; Gene Expression Regulation/drug effects ; Humans ; LIM Domain Proteins ; Leukocytes, Mononuclear/pathology ; Measles virus ; Mice ; Mice, Transgenic ; Nucleocapsid Proteins/genetics ; Nucleocapsid Proteins/pharmacology ; Osteitis Deformans/pathology ; Osteoclasts/drug effects ; Osteoclasts/pathology ; Proteasome Endopeptidase Complex ; RANK Ligand/pharmacology ; TNF Receptor-Associated Factor 2/genetics ; Transcription Factors/pharmacology ; Transduction, Genetic
Chemical Substances	Adaptor Proteins, Signal Transducing ; LIM Domain Proteins ; Nucleocapsid Proteins ; PSMC5 protein, human ; RANK Ligand ; TNF Receptor-Associated Factor 2 ; Transcription Factors ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-)
Language	English
Publishing date	2008-03-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.21723
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Article: Oral L-arginine supplementation ameliorates urinary risk factors and kinetic modulation of Tamm-Horsfall glycoprotein in experimental hyperoxaluric rats.

Pragasam, Viswanathan / Kalaiselvi, Periandavan / Sumitra, Kamalanathan / Srinivasan, Shanmugarajan / Varalakshmi, Palaninathan

Clinica chimica acta; international journal of clinical chemistry

2005 Volume 360, Issue 1-2, Page(s) 141–150

Abstract: Background: Oral supplementation of l-arginine (l-arg) is found to be beneficial in many kidney disorders. We determined whether l-arg supplementation safeguards the renal epithelial cell damage induced by hyperoxaluria with excretion of urinary marker ... ...

Abstract	Background: Oral supplementation of l-arginine (l-arg) is found to be beneficial in many kidney disorders. We determined whether l-arg supplementation safeguards the renal epithelial cell damage induced by hyperoxaluria with excretion of urinary marker enzymes and lithogenic salts with special reference to Tamm-Horsfall glycoprotein (THP). Methods: Hyperoxaluria was induced by 0.75% ethylene glycol (EG) in drinking water. l-Arg was co-supplemented at the dose of 1.25 g/kg b.w. orally for 28 days. At the end of experimental period, 24-h urine samples were collected in all the experimental groups. Isolation and purification of THP was carried in rat urine and were subjected to spectrophotometric crystallization assay and calcium-(14)C-oxalate binding studies. Determination of the lithogenic risk factors like calcium, oxalate, phosphorus, citrate, and marker enzymes such as lactate dehydrogenase (LDH) and gamma-glutamyltransferase (gamma-GT) were carried out in the collected urine sample. Results: Urinary excretion of calcium and oxalate was significantly increased in EG-treated rats. In l-arg supplemented hyperoxaluric rats, these concentrations were significantly (p<0.001) decreased when compared to that of hyperoxaluric rats, and were moderately elevated from that of control rats. The activities of urinary marker enzymes, both LDH and gamma-GT were 2-fold increased in EG-treated rats, when compared to control rats, but these values were maintained near normal in l-arg supplemented EG-treated rats. Citrate excretion was enhanced in the l-arg co-supplemented hyperoxaluric rats. In spectrophotometric crystallization assay system, l-arg supplemented rat THP showed inhibition in nucleation and aggregation phases, whereas EG-treated rat THP showed promotion of both calcium oxalate nucleation and aggregation phases. In calcium-(14)C-oxalate binding assay, THP derived from hyperoxaluric rats exhibited 2-fold increase (p<0.001) in the CaOx binding when compared to control and l-arg supplemented animals. Conclusions:* l-Arg could act as a potent antilithic agent, by increasing the level of citrate in the hyperoxaluria-induced rats and decreasing calcium oxalate binding to the THP. l-Arg also effectively prevents the deposition of calcium oxalate crystals by curtailing the renal epithelial damage and protein oxidation as evidenced by the normal activities of urinary marker enzymes in l-arg supplemented hyperoxaluric rats.
MeSH term(s)	Animals ; Arginine/administration & dosage ; Biomarkers/urine ; Calcium Compounds/analysis ; Calcium Oxalate/metabolism ; Citric Acid/urine ; Clinical Enzyme Tests ; Dietary Supplements ; Epithelial Cells/drug effects ; Epithelial Cells/pathology ; Ethylene Glycol ; Hyperoxaluria/chemically induced ; Hyperoxaluria/drug therapy ; Hyperoxaluria/urine ; Kidney/pathology ; Male ; Mucoproteins/isolation & purification ; Mucoproteins/metabolism ; Mucoproteins/urine ; Oxides/analysis ; Protective Agents/administration & dosage ; Rats ; Rats, Wistar ; Risk Factors ; Uromodulin
Chemical Substances	Biomarkers ; Calcium Compounds ; Mucoproteins ; Oxides ; Protective Agents ; Umod protein, rat ; Uromodulin ; Calcium Oxalate (2612HC57YE) ; Citric Acid (2968PHW8QP) ; Arginine (94ZLA3W45F) ; lime (C7X2M0VVNH) ; Ethylene Glycol (FC72KVT52F)
Language	English
Publishing date	2005-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80228-1
ISSN	1873-3492 ; 0009-8981
ISSN (online)	1873-3492
ISSN	0009-8981
DOI	10.1016/j.cccn.2005.04.016
Database	MEDical Literature Analysis and Retrieval System OnLINE

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