Related Experiment Video

Updated: Mar 8, 2026

A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation
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A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation

Published on: March 15, 2018

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RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis

Kelsi Andrade1, Jaime Fornetti1, Ling Zhao1

  • 1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Science Translational Medicine
|January 27, 2017
PubMed

Insights

Macrophage-stimulating protein (MSP) signaling via RON kinase directly activates osteoclasts, promoting bone destruction in cancer and osteoporosis. Inhibiting RON kinase offers a new therapeutic strategy for bone loss diseases.

Area of Science:

  • Oncology
  • Bone Biology
  • Molecular Signaling

Background:

  • Bone destruction, or osteolysis, is a hallmark of aging and diseases like osteoporosis and cancer, often proving resistant to current treatments.
  • Existing therapies target osteoclast activity by inhibiting bisphosphonates or the receptor activator of nuclear factor κB ligand (RANKL) pathway.
  • Macrophage-stimulating protein (MSP) signaling, prevalent in breast cancer, exacerbates osteolytic bone metastasis through tumor cell or bone microenvironment activation.

Purpose of the Study:

  • To elucidate the mechanism by which MSP signaling contributes to osteolytic bone metastasis.
  • To identify novel therapeutic targets for treating bone destruction associated with aging and disease.
  • To investigate the efficacy of targeting the MSP-RON signaling pathway in preclinical models and human studies.

Main Methods:

  • Investigated MSP signaling through its receptor, RON tyrosine kinase, on host cells.
  • Examined the direct activation of osteoclasts via a novel pathway involving RON and SRC (proto-oncogene, non-receptor tyrosine kinase).
  • Utilized genetic and pharmacologic inhibition of RON kinase in mouse models of cancer-mediated bone destruction and osteoporosis.
  • Assessed the effects of the RON kinase inhibitor BMS-777607/ASLAN002 on bone turnover markers in a human clinical trial.

Main Results:

  • MSP signals through RON tyrosine kinase on host cells to directly activate osteoclasts, a pathway complementary to RANKL signaling and converging on SRC.
  • Genetic or pharmacologic inhibition of RON kinase effectively blocked cancer-induced bone destruction and osteoporosis in multiple mouse models.
  • The RON kinase inhibitor BMS-777607/ASLAN002 demonstrated potential by altering bone turnover markers in a human clinical cancer study.

Conclusions:

  • Uncovered a novel MSP-RON-SRC signaling axis that directly drives osteoclast activation and pathogenic bone loss.
  • Demonstrated that RON kinase is a viable therapeutic target for combating bone destruction in various diseases, including osteoporosis and cancer metastasis.
  • Provided a strong rationale for developing and utilizing RON inhibitors for the treatment of bone loss conditions.

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