Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo

J. Teramachi, R. Silbermann, P. Yang, W. Zhao, Khalid Mohammad, J. Guo, J. L. Anderson, D. Zhou, R. Feng, K. Z. Myint, Nathan Maertz, J. H. Beumer, J. L. Eiseman, J. J. Windle, X. Q. Xie, G. David Roodman, Noriyoshi Kurihara

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2's capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.

Original languageEnglish (US)
Pages (from-to)390-398
Number of pages9
JournalLeukemia
Volume30
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Osteoclasts
Multiple Myeloma
Osteogenesis
Bone and Bones
Growth
Mesenchymal Stromal Cells
Bone Diseases
In Vitro Techniques
Osteoblasts
Up-Regulation
Tumor Necrosis Factor-alpha
Bone Marrow
Cell Line

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo. / Teramachi, J.; Silbermann, R.; Yang, P.; Zhao, W.; Mohammad, Khalid; Guo, J.; Anderson, J. L.; Zhou, D.; Feng, R.; Myint, K. Z.; Maertz, Nathan; Beumer, J. H.; Eiseman, J. L.; Windle, J. J.; Xie, X. Q.; Roodman, G. David; Kurihara, Noriyoshi.

In: Leukemia, Vol. 30, No. 2, 01.02.2016, p. 390-398.

Research output: Contribution to journalArticle

Teramachi, J, Silbermann, R, Yang, P, Zhao, W, Mohammad, K, Guo, J, Anderson, JL, Zhou, D, Feng, R, Myint, KZ, Maertz, N, Beumer, JH, Eiseman, JL, Windle, JJ, Xie, XQ, Roodman, GD & Kurihara, N 2016, 'Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo', Leukemia, vol. 30, no. 2, pp. 390-398. https://doi.org/10.1038/leu.2015.229
Teramachi, J. ; Silbermann, R. ; Yang, P. ; Zhao, W. ; Mohammad, Khalid ; Guo, J. ; Anderson, J. L. ; Zhou, D. ; Feng, R. ; Myint, K. Z. ; Maertz, Nathan ; Beumer, J. H. ; Eiseman, J. L. ; Windle, J. J. ; Xie, X. Q. ; Roodman, G. David ; Kurihara, Noriyoshi. / Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo. In: Leukemia. 2016 ; Vol. 30, No. 2. pp. 390-398.
@article{09912e82ee3649a5b83324f0babc10b3,
title = "Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo",
abstract = "We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2's capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.",
author = "J. Teramachi and R. Silbermann and P. Yang and W. Zhao and Khalid Mohammad and J. Guo and Anderson, {J. L.} and D. Zhou and R. Feng and Myint, {K. Z.} and Nathan Maertz and Beumer, {J. H.} and Eiseman, {J. L.} and Windle, {J. J.} and Xie, {X. Q.} and Roodman, {G. David} and Noriyoshi Kurihara",
year = "2016",
month = "2",
day = "1",
doi = "10.1038/leu.2015.229",
language = "English (US)",
volume = "30",
pages = "390--398",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo

AU - Teramachi, J.

AU - Silbermann, R.

AU - Yang, P.

AU - Zhao, W.

AU - Mohammad, Khalid

AU - Guo, J.

AU - Anderson, J. L.

AU - Zhou, D.

AU - Feng, R.

AU - Myint, K. Z.

AU - Maertz, Nathan

AU - Beumer, J. H.

AU - Eiseman, J. L.

AU - Windle, J. J.

AU - Xie, X. Q.

AU - Roodman, G. David

AU - Kurihara, Noriyoshi

PY - 2016/2/1

Y1 - 2016/2/1

N2 - We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2's capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.

AB - We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2's capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.

UR - http://www.scopus.com/inward/record.url?scp=84959352838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959352838&partnerID=8YFLogxK

U2 - 10.1038/leu.2015.229

DO - 10.1038/leu.2015.229

M3 - Article

C2 - 26286116

AN - SCOPUS:84959352838

VL - 30

SP - 390

EP - 398

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 2

ER -