Regulation of bone homeostasis by MERTK and TYRO3

Janik Engelmann, Jennifer Zarrer, Victoria Gensch, Kristoffer Riecken, Nikolaus Berenbrok, The Vinh Luu, Antonia Beitzen-Heineke, Maria Elena Vargas-Delgado, Klaus Pantel, Carsten Bokemeyer, Somasekhar Bhamidipati, Ihab S. Darwish, Esteban Masuda, Tal Burstyn-Cohen, Emily J. Alberto, Sourav Ghosh, Carla Rothlin, Eric Hesse, Hanna Taipaleenmäki, Isabel Ben-Batalla () and Sonja Loges ()
Additional contact information
Janik Engelmann: University Medical Center Hamburg-Eppendorf
Jennifer Zarrer: University Medical Center Hamburg-Eppendorf
Victoria Gensch: University Medical Center Hamburg-Eppendorf
Kristoffer Riecken: University Medical Center Hamburg-Eppendorf
Nikolaus Berenbrok: University Medical Center Hamburg-Eppendorf
The Vinh Luu: University Medical Center Hamburg-Eppendorf
Antonia Beitzen-Heineke: University Medical Center Hamburg-Eppendorf
Maria Elena Vargas-Delgado: University Medical Center Hamburg-Eppendorf
Klaus Pantel: University Medical Center Hamburg-Eppendorf
Carsten Bokemeyer: University Medical Center Hamburg-Eppendorf
Somasekhar Bhamidipati: Rigel Pharmaceuticals, Inc.
Ihab S. Darwish: Rigel Pharmaceuticals, Inc.
Esteban Masuda: Rigel Pharmaceuticals, Inc.
Tal Burstyn-Cohen: The Hebrew University of Jerusalem
Emily J. Alberto: Yale University School of Medicine
Sourav Ghosh: Yale University School of Medicine
Carla Rothlin: Yale University School of Medicine
Eric Hesse: University Hospital, LMU Munich
Hanna Taipaleenmäki: University Medical Center Hamburg-Eppendorf
Isabel Ben-Batalla: University Medical Center Hamburg-Eppendorf
Sonja Loges: University Medical Center Hamburg-Eppendorf

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33938-x

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DOI: 10.1038/s41467-022-33938-x

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