Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness

JCI Insight. 2019 Apr 9;5(9):e125543. doi: 10.1172/jci.insight.125543.

Abstract

Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined the expression of sclerostin, a soluble Wnt inhibitor that represses osteoblast differentiation and bone formation. In mice with breast cancer bone metastases, pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and reducing osteoclast-dependent bone resorption. During advanced disease, NF-κB and p38 signaling was increased in muscles in a TGF-β1-dependent manner, causing muscle fiber atrophy, muscle weakness and tissue regeneration with an increase in Pax7-positive satellite cells. Scl-Ab treatment restored NF-κB and p38 signaling, the abundance of Pax7-positive cells and ultimately muscle function. These effects improved the overall health condition and expanded the life span of cancer-bearing mice. Together, these results demonstrate that pharmacological inhibition of sclerostin reduces bone metastatic burden and muscle weakness with a prolongation of the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. .

Keywords: Bone Biology; Bone disease; Breast cancer; Oncology; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / drug effects*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Benzothiazoles
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Bone Resorption / prevention & control
  • Bone and Bones / pathology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Mice
  • Mice, SCID
  • Muscle Weakness / pathology
  • NF-kappa B / metabolism
  • Osteoblasts / metabolism
  • Osteoclasts
  • Osteogenesis / drug effects
  • PAX7 Transcription Factor / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Immunological
  • Benzothiazoles
  • IWP-2 compound
  • NF-kappa B
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Sost protein, mouse

Grant support

HT is funded by a grant TA 1154/1-1 and HE by grants HE 5208/2-1 and HE 5208/2-3