CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation

Dongzheng Gai; Jin-Ran Chen; James P. Stewart; Intawat Nookaew; Hasem Habelhah; Cody Ashby; Fumou Sun; Yan Cheng; Can Li; Hongwei Xu; Bailu Peng; Tarun K. Garg; Carolina Schinke; Sharmilan Thanendrarajan; Maurizio Zangari; Fangping Chen; Bart Barlogie; Frits van Rhee; Guido Tricot; John D. Shaughnessy Jr; Fenghuang Zhan

doi:10.1172/JCI159527

¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Peng, B. in: JCI | PubMed | Google Scholar

¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Chen, F. in: JCI | PubMed | Google Scholar |

¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Barlogie, B. in: JCI | PubMed | Google Scholar

¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

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¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Tricot, G. in: JCI | PubMed | Google Scholar

¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Shaughnessy Jr, J. in: JCI | PubMed | Google Scholar

¹Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

²Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, United States of America

³Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, United States of America

⁴Department of Pathology, University of Iowa, Iowa City, United States of America

⁵Department of Hematology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Zhan, F. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI159527.
Copyright © 2022, Gai et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published July 26, 2022 - Version history

Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OL). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified bone marrow (BM) CD138⁺ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K, and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single cell RNA-sequencing identified that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss.

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CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation

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