STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex

Jeong, Eutteum; Choi, Han Kyoung; Park, Jin Hee; Lee, Soo Young

doi:10.1038/s41418-017-0048-5

Cited by 26 publications

(21 citation statements)

References 46 publications

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“…One possibility is that stac abundance may be tuned developmentally ( Suzuki et al, 1996 ), pathologically, or via interacting proteins ( Satoh et al, 2006 ). For instance, the transcription factor, NFAT binds to an upstream promoter region of stac2 gene to upregulate stac2 expression in osteoclasts as well as during hypoxic conditions in neural stem cells ( Jeong et al, 2018 ; Moreno et al, 2015 ). Physiologically, as Ca V 1 CDI is a potent homeostatic mechanism that prevents pathological Ca 2+ -overload ( Dunlap, 2007 ), a low concentration regime of stac may be advantageous.…”

Section: Discussionmentioning

confidence: 99%

Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Niu

Dick

Yang

et al. 2018

eLife

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Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca2+/CaM-regulation of CaV1 and NaV1 families, respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from the CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into CaV1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca2+/CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca2+/CaM signaling to individual targets.

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Section: Discussionmentioning

confidence: 99%

Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Niu

Dick

Yang

et al. 2018

eLife

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“…BMMs from murine bone marrow precursors derived from six-to eight-week-old male C57BL/6 mice (The Jackson Laboratory) were prepared as previously described [52]. BMMs were treated with M-CSF (30 ng/mL) and RANKL (100 ng/mL) for three to four days, and matured osteoclasts were fixed and stained for the presence of tartrate-resistant acid phosphatase (TRAP) with a TRAP staining kit (Sigma-Aldrich).…”

Section: Osteoclast Differentiationmentioning

confidence: 99%

Plasma proteomic profiling of young and old mice reveals cadherin-13 prevents age-related bone loss

Yang

Kabir

Park

et al. 2020

Aging

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The blood exhibits a dynamic flux of proteins that are secreted by the tissues and cells of the body. To identify novel aging-related circulating proteins, we compared the plasma proteomic profiles of young and old mice using tandem mass spectrometry. The expression of 134 proteins differed between young and old mice. We selected seven proteins that were expressed at higher levels in young mice, and confirmed their plasma expression in immunoassays. The plasma levels of anthrax toxin receptor 2 (ANTXR2), cadherin-13 (CDH-13), scavenger receptor cysteine-rich type 1 protein M130 (CD163), cartilage oligomeric matrix protein (COMP), Dickkopf-related protein 3 (DKK3), periostin, and secretogranin-1 were all confirmed to decrease with age. We then investigated whether any of the secreted proteins influenced bone metabolism and found that CDH-13 inhibited osteoclast differentiation. CDH 13 treatment suppressed the receptor activator of NF-κB ligand (RANKL) signaling pathway in bone marrow-derived macrophages, and intraperitoneal administration of CDH-13 delayed age-related bone loss in the femurs of aged mice. These findings suggest that low plasma CDH-13 expression in aged mice promotes aging-associated osteopenia by facilitating excessive osteoclast formation. Thus, CDH-13 could have therapeutic potential as a protein drug for the prevention of osteopenia.

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“…8). Notably, transcription factors that regulate osteoclast formation maintain bone development and metabolism under physiological conditions and regulate bone loss under pathological conditions, such as inflammatory states 29,30 . Further research regarding the pathophysiological roles played by Spi-C remains necessary to understand whether Spi-C acts as a key transcriptional regulator that promotes osteoclast formation.…”

Section: Discussionmentioning

confidence: 99%

Spi-C positively regulates RANKL-mediated osteoclast differentiation and function

Park

et al. 2020

Exp Mol Med

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Spi-C is an SPI-group erythroblast transformation-specific domain transcription factor expressed during B-cell development. Here, we report that Spi-C is a novel receptor activator of nuclear factor-κB ligand (RANKL)-inducible protein that positively regulates RANKL-mediated osteoclast differentiation and function. Knockdown of Spi-C decreased the expression of RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1, receptor activator of nuclear factor-κB (RANK), and tartrate-resistant acid phosphatase (TRAP), resulting in a marked decrease in the number of TRAP-positive multinucleated cells. Spi-C-transduced bone marrow-derived monocytes/macrophages (BMMs) displayed a significant increase in osteoclast formation in the presence of RANKL. In addition, Spi-C-depleted cells failed to show actin ring formation or bone resorption owing to a marked reduction in the expression of RANKL-mediated dendritic cell-specific transmembrane protein and the d2 isoform of vacuolar (H+) ATPase V0 domain, which are known osteoclast fusion-related genes. Interestingly, RANKL stimulation induced the translocation of Spi-C from the cytoplasm into the nucleus during osteoclastogenesis, which was specifically blocked by inhibitors of p38 mitogen-activated protein kinase (MAPK) or PI3 kinase. Moreover, Spi-C depletion prevented RANKL-induced MAPK activation and the degradation of inhibitor of κB-α (IκBα) in BMMs. Collectively, these results suggest that Spi-C is a novel positive regulator that promotes both osteoclast differentiation and function.

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STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex

Cited by 26 publications

References 46 publications

Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Plasma proteomic profiling of young and old mice reveals cadherin-13 prevents age-related bone loss

Spi-C positively regulates RANKL-mediated osteoclast differentiation and function

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