Journal article
CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation
The Journal of clinical investigation, Vol.132(18), e159527
09/15/2022
DOI: 10.1172/JCI159527
PMCID: PMC9479617
PMID: 35881476
Abstract
Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). 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 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-Seq showed 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.
Details
- Title: Subtitle
- CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation
- Creators
- Dongzheng GaiJin-Ran ChenJames P StewartIntawat NookaewHasem HabelhahCody AshbyFumou SunYan ChengCan LiHongwei XuBailu PengTarun K GargCarolina SchinkeSharmilan ThanendrarajanMaurizio ZangariFangping ChenBart BarlogieFrits van RheeGuido TricotJohn D ShaughnessyFenghuang Zhan
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.132(18), e159527
- DOI
- 10.1172/JCI159527
- PMID
- 35881476
- PMCID
- PMC9479617
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: R01 CA236814; DOI: 10.13039/100000005, name: US Department of Defense, award: CA180190
- Language
- English
- Date published
- 09/15/2022
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Internal Medicine
- Record Identifier
- 9984296161602771
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