CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation
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 CD1...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-09-01
|
| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI159527 |
| _version_ | 1797634625057587200 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Dongzheng Gai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:10:12Z |
| format | Article |
| id | doaj.art-e0033236077b4a64b805c9d221f71dcc |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:10:12Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-e0033236077b4a64b805c9d221f71dcc2023-11-07T16:19:21ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-09-0113218CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiationDongzheng GaiJin-Ran ChenJames P. StewartIntawat NookaewHasem HabelhahCody AshbyFumou SunYan ChengCan LiHongwei XuBailu PengTarun K. GargCarolina SchinkeSharmilan ThanendrarajanMaurizio ZangariFangping ChenBart BarlogieFrits van RheeGuido TricotJohn D. Shaughnessy Jr.Fenghuang ZhanOsteolytic 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.https://doi.org/10.1172/JCI159527Bone BiologyHematology |
| spellingShingle | 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 CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation The Journal of Clinical Investigation Bone Biology Hematology |
| title | CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation |
| title_full | CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation |
| title_fullStr | CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation |
| title_full_unstemmed | CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation |
| title_short | CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation |
| title_sort | cst6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation |
| topic | Bone Biology Hematology |
| url | https://doi.org/10.1172/JCI159527 |
| work_keys_str_mv | AT dongzhenggai cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT jinranchen cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT jamespstewart cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT intawatnookaew cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT hasemhabelhah cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT codyashby cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT fumousun cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT yancheng cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT canli cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT hongweixu cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT bailupeng cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT tarunkgarg cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT carolinaschinke cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT sharmilanthanendrarajan cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT mauriziozangari cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT fangpingchen cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT bartbarlogie cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT fritsvanrhee cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT guidotricot cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT johndshaughnessyjr cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation AT fenghuangzhan cst6suppressesosteolyticbonediseaseinmultiplemyelomabyblockingosteoclastdifferentiation |