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

J Clin Invest. 2022 Sep 15;132(18):e159527. doi: 10.1172/JCI159527.


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.

Keywords: Bone Biology; Bone disease; Cancer; Hematology; Osteoclast/osteoblast biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bone Resorption* / genetics
  • Bone Resorption* / metabolism
  • Cell Differentiation / physiology
  • Cystatin M / metabolism
  • Humans
  • Multiple Myeloma* / complications
  • Multiple Myeloma* / genetics
  • Multiple Myeloma* / metabolism
  • Osteoclasts / metabolism
  • Osteolysis* / genetics
  • Osteolysis* / metabolism
  • Positron Emission Tomography Computed Tomography
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • TNF Receptor-Associated Factor 3 / metabolism


  • CST6 protein, human
  • Cystatin M
  • RANK Ligand
  • TNF Receptor-Associated Factor 3