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; Sonja Loges

doi:10.1038/s41467-022-33938-x

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^*Sonja Loges^*

^*Corresponding author for this work

Institute of Biomedical Research at the Faculty of Dental Medicine

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English
Article number	7689
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33938-x
State	Published - 12 Dec 2022

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Publisher Copyright:
© 2022, The Author(s).

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Engelmann, J., Zarrer, J., Gensch, V., Riecken, K., Berenbrok, N., Luu, T. V., Beitzen-Heineke, A., Vargas-Delgado, M. E., Pantel, K., Bokemeyer, C., Bhamidipati, S., Darwish, I. S., Masuda, E., Burstyn-Cohen, T., Alberto, E. J., Ghosh, S., Rothlin, C., Hesse, E., Taipaleenmäki, H., ... Loges, S. (2022). Regulation of bone homeostasis by MERTK and TYRO3. Nature Communications, 13(1), Article 7689. https://doi.org/10.1038/s41467-022-33938-x

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title = "Regulation of bone homeostasis by MERTK and TYRO3",

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.",

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Engelmann, J, Zarrer, J, Gensch, V, Riecken, K, Berenbrok, N, Luu, TV, Beitzen-Heineke, A, Vargas-Delgado, ME, Pantel, K, Bokemeyer, C, Bhamidipati, S, Darwish, IS, Masuda, E, Burstyn-Cohen, T, Alberto, EJ, Ghosh, S, Rothlin, C, Hesse, E, Taipaleenmäki, H, Ben-Batalla, I & Loges, S 2022, 'Regulation of bone homeostasis by MERTK and TYRO3', Nature Communications, vol. 13, no. 1, 7689. https://doi.org/10.1038/s41467-022-33938-x

TY - JOUR

T1 - Regulation of bone homeostasis by MERTK and TYRO3

AU - Engelmann, Janik

AU - Zarrer, Jennifer

AU - Gensch, Victoria

AU - Riecken, Kristoffer

AU - Berenbrok, Nikolaus

AU - Luu, The Vinh

AU - Beitzen-Heineke, Antonia

AU - Vargas-Delgado, Maria Elena

AU - Pantel, Klaus

AU - Bokemeyer, Carsten

AU - Bhamidipati, Somasekhar

AU - Darwish, Ihab S.

AU - Masuda, Esteban

AU - Burstyn-Cohen, Tal

AU - Alberto, Emily J.

AU - Ghosh, Sourav

AU - Rothlin, Carla

AU - Hesse, Eric

AU - Taipaleenmäki, Hanna

AU - Ben-Batalla, Isabel

AU - Loges, Sonja

PY - 2022/12/12

Y1 - 2022/12/12

N2 - 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.

AB - 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.

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Regulation of bone homeostasis by MERTK and TYRO3

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