Secretion of a Truncated Osteopetrosis-associated Transmembrane Protein 1 (OSTM1) Mutant Inhibits Osteoclastogenesis through Down-regulation of the B Lymphocyte-induced Maturation Protein 1 (BLIMP1)-Nuclear Factor of Activated T Cells c1 (NFATc1) Axis

Shin, Bongjin; Yu, Jungeun; Park, Eui‐Soon; Choi, Seunga; Yu, Ji‐Yeon; Hwang, Jung Me; Yun, Hyo In; Chung, Young‐Ho; Hong, Kwan Soo; Choi, Jong‐Soon; Miki, Takami; Rho, Jaerang

doi:10.1074/jbc.m114.589614

Cited by 24 publications

(39 citation statements)

References 35 publications

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“…Also, this secreted Ostm1 binds to osteoclast precursors and inhibits osteoclastogenesis (Shin et al . ). Ostm1 has been identified as a target of miR‐140 in pluripotent stem cells in response to bone morphogenetic protein‐4 (BMP4) treatment, which promotes adipocyte lineage commitment; thus, Ostm1 would work as an anti‐adipogenic factor in this system, and it would also potentially link BMP and Wnt signalling pathways (Liu et al .…”

Section: Ostm1 and Clc‐7mentioning

confidence: 97%

Regulatory–auxiliary subunits of CLC chloride channel–transport proteins

Barrallo-Gimeno

Gradogna

Zanardi

et al. 2015

The Journal of Physiology

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The CLC family of chloride channels and transporters is composed by nine members, but only three of them, ClC-Ka/b, ClC-7 and ClC-2, have been found so far associated with auxiliary subunits. These CLC regulatory subunits are small proteins that present few common characteristics among them, both structurally and functionally, and their effects on the corresponding CLC protein are different. Barttin, a protein with two transmembrane domains, is essential for the membrane localization of ClC-K proteins and their activity in the kidney and inner ear. Ostm1 is a protein with a single transmembrane domain and a highly glycosylated N-terminus. Unlike the other two CLC auxiliary subunits, Ostm1 shows a reciprocal relationship with ClC-7 for their stability. The subcellular localization of Ostm1 depends on ClC-7 and not the other way around. ClC-2 is active on its own, but GlialCAM, a transmembrane cell adhesion molecule with two extracellular immunoglobulin (Ig)-like domains, regulates its subcellular localization and activity in glial cells. The common theme for these three proteins is their requirement for a proper homeostasis, since their malfunction leads to distinct diseases. We will review here their properties and their role in normal chloride physiology and the pathological consequences of their improper function.

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Section: Ostm1 and Clc‐7mentioning

confidence: 97%

Regulatory–auxiliary subunits of CLC chloride channel–transport proteins

Barrallo-Gimeno

Gradogna

Zanardi

et al. 2015

The Journal of Physiology

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“…The expression plasmid of HA-tagged ubiquitin (HA-Ub) was described previously (38,39). For the Vav3 knockdown (Vav3 KD ) plasmid DNA, a shRNA targeting the murine Vav3 gene was designed as previously described (39) Osteoclastogenesis and OC Analysis-Murine BMMs were prepared as previously described (37,41). In brief, bone marrow cells isolated from the femurs of 8-week-old C57BL/6 male mice were differentiated into BMMs by culturing them in ␣-minimum essential medium containing 10% FBS and M-CSF (150 ng/ml) for 2 days.…”

Section: Methodsmentioning

confidence: 99%

“…Protein G beads were purchased from Amersham Biosciences-Pharmacia Biotech. Recombinant human soluble RANKL and human M-CSF were described previously (36,37). 293T and PlatE cells were cultured in DMEM (Welgene, Daegue, Korea) supplemented with 10% FBS (Invitrogen) and an antibiotic/antimycotic solution (Welgene) at 37°C in a 5% CO 2 atmosphere.…”

Section: Methodsmentioning

confidence: 99%

“…Analysis of the RANKL-induced signaling pathway was performed as previously described (37,41). For the bone resorbing activity of OCs, retroviral-transduced BMMs (1.5 ϫ 10 4 cells/well) were cultured with M-CSF (50 ng/ml) and RANKL (100 ng/ml) or the anti-human CD40 monoclonal antibody G28 -5 (100 ng/ml) on dentin slices for 3-6 days, as previously described (37,41). The cells were removed with 10% sodium hypochlorite solution to permit observation of the resorption pit.…”

Section: Methodsmentioning

confidence: 99%

“…The resorption pit was stained with 1% toluidine blue and photographed under a microscope, and the resorbing activity was evaluated by measuring the area of the resorption pit. To analyze osteoclastogenic gene expression, real time PCR was performed as previously described (37,41). The primers used for real time PCR amplification were as follows: TRAP (sense), 5Ј-AAA TCA CTC TTC AAG ACC AG-3Ј; TRAP (antisense), 5Ј-TTA TTG AAC AGC AGT GAC AG-3Ј; DC-STAMP (sense), 5Ј-TCC TCC ATG AAC AAA CAG TTC CAA-3Ј; DC-STAMP (antisense), 5Ј-AGA CGT GGT TTA GGA ATG CAG CTC-3Ј; Atp6v0d2 (sense), 5Ј-TTC AGT TGC TAT CCA GGA CTC GGA-3Ј; Atp6v0d2 (antisense), 5Ј-GCA TGT CAT GTA GGT GAG AAA TGT GCT CA-3Ј; OSCAR (sense), 5Ј-TCT GCC CCC TAT GTG CTA TCA-3Ј; and OSCAR (antisense), 5Ј-AGG AGC CAG AAC CTT CGA AAC-3Ј.…”

Section: Methodsmentioning

confidence: 99%

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Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis

Yun

Shin

et al. 2016

Journal of Biological Chemistry

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The signaling pathway downstream of stimulation of receptor activator of nuclear factor B (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANK cyto ) to trigger downstream osteoclastogenic signaling cascades. RANK cyto harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANK cyto mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANK cyto mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANK cyto enhances downstream NF-B, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK-mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex.The integrity of the skeletal system is maintained by the process of bone remodeling, in which old and damaged bone is continuously replaced with new bone through the balanced action of bone-resorbing osteoclasts (OCs) 3 and bone-forming osteoblasts (1-3). As the only cells with bone-resorbing activity, OCs are clinically important in bone-related diseases; accelerated bone destruction by OCs results in pathological bone loss associated with rheumatoid arthritis, multiple myeloma, metastatic cancer, and osteoporosis, whereas impaired function of OCs leads to osteopetrotic disorders (2, 4).OCs are multinucleated giant cells that are formed by the fusion of monocyte/macrophage lineage precursors through the process of OC differentiation or osteoclastogenesis (2). The signaling pathways of receptor activator of nuclear factor B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play key roles in osteoclastogenesis (2, 5). Mice lacking either RANK or RANKL exhibit severe osteopetrotic phenotypes, highlighting the importance of RANK-RANKL signaling as a crucial regulator of OC differentiation, activation, and survival (6, 7). RANK-RANKL signaling is initiated primarily by the recruitment of cytoplasmic TNF receptor-associated factors (TRAFs) that trigger the activation of signaling cascades downstream of adaptors/kinases, such as nuclear fa...

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The clinical features of OSTM1‐associated malignant infantile osteopetrosis: A retrospective, single‐center experience over one decade

Alotaibi¹,

Dighe²,

Aldaihani³

2022

American J of Med Genetics Pt A

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Mutation in OSTM1 give rise to the rarest and most lethal subtype of malignant infantile osteopetrosis (MIOP), and an improved understanding of OSTM1‐associated MIOP would help with informed decision‐making regarding symptom management and early palliative care referral. This retrospective study describes the clinical and laboratory features of patients with a genetic diagnosis of OSTM1 MIOP made between January 2011 and December 2021 in the Department of Pediatrics, Al‐Adan Hospital, Kuwait. Twenty‐two children had confirmed homozygous deletion in OSTM1 (13 females, nine males). Consanguinity was reported in almost all parents. 72.7% were diagnosed before the age of two months, most commonly incidentally with a high clinical suspicion. All 22 patients developed upper respiratory symptoms, hepatosplenomegaly, poor feeding, and had severe developmental delay. 80% of patients developed pain and/or irritability, and 40.9% were diagnosed with primary seizures. Bone fractures developed in 27% of patients, most likely iatrogenic, and some patients had hernia and gum abnormalities. The mean survival was 10.9 months. The clinical presentation, symptomatology, and mortality of our cohort were compared with other cases of OSTM1 MIOP identified through a comperhensive search of the PubMed database. The findings conclude that OSTM1 MIOP is a multi‐systemic disease with distinct clinical features, of which neurological complications are the most severe and include nociplastic pain and irritability. Although orthopedic complications influence the trajectory of most patients with other forms of osteopetrosis, OSTM1 MIOP is driven by its neurological complications. Hence, OSTM1 should be regarded as a neurodegenerative disease with osteopetrosis as a comorbidity that warrants early palliative care referral.

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Secretion of a Truncated Osteopetrosis-associated Transmembrane Protein 1 (OSTM1) Mutant Inhibits Osteoclastogenesis through Down-regulation of the B Lymphocyte-induced Maturation Protein 1 (BLIMP1)-Nuclear Factor of Activated T Cells c1 (NFATc1) Axis

Cited by 24 publications

References 35 publications

Regulatory–auxiliary subunits of CLC chloride channel–transport proteins

Regulatory–auxiliary subunits of CLC chloride channel–transport proteins

Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis

The clinical features of OSTM1‐associated malignant infantile osteopetrosis: A retrospective, single‐center experience over one decade

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