Research ExplorerPublicationsRegulation of bone homeostasis by MERTK and TYRO3

Regulation of bone homeostasis by MERTK and TYRO3

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Regulation of bone homeostasis by MERTK and TYRO3. / Engelmann, Janik; Zarrer, Jennifer; Gensch, Victoria; Riecken, Kristoffer; Berenbrok, Nikolaus; Luu, The Vinh; Beitzen-Heineke, Antonia; Vargas-Delgado, Maria Elena; Pantel, Klaus; Bokemeyer, Carsten; Bhamidipati, Somasekhar; Darwish, Ihab S; Masuda, Esteban; Burstyn-Cohen, Tal; Alberto, Emily J; Ghosh, Sourav; Rothlin, Carla; Hesse, Eric; Taipaleenmäki, Hanna; Ben Batalla, Isabel; Loges, Sonja.

In: NAT COMMUN, Vol. 13, No. 1, 7689, 12.12.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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', NAT COMMUN, vol. 13, no. 1, 7689. https://doi.org/10.1038/s41467-022-33938-x

APA

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. NAT COMMUN, 13(1), [7689]. https://doi.org/10.1038/s41467-022-33938-x

Vancouver

Engelmann J, Zarrer J, Gensch V, Riecken K, Berenbrok N, Luu TV et al. Regulation of bone homeostasis by MERTK and TYRO3. NAT COMMUN. 2022 Dec 12;13(1). 7689. https://doi.org/10.1038/s41467-022-33938-x

Bibtex

@article{e89914f0fd494f0f96d7cbabf6946502,
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.",
keywords = "Mice, Animals, c-Mer Tyrosine Kinase/genetics, Receptor Protein-Tyrosine Kinases/metabolism, Proto-Oncogene Proteins/metabolism, Homeostasis, Carrier Proteins",
author = "Janik Engelmann and Jennifer Zarrer and Victoria Gensch and Kristoffer Riecken and Nikolaus Berenbrok and Luu, {The Vinh} and Antonia Beitzen-Heineke and Vargas-Delgado, {Maria Elena} and Klaus Pantel and Carsten Bokemeyer and Somasekhar Bhamidipati and Darwish, {Ihab S} and Esteban Masuda and Tal Burstyn-Cohen and Alberto, {Emily J} and Sourav Ghosh and Carla Rothlin and Eric Hesse and Hanna Taipaleenm{\"a}ki and {Ben Batalla}, Isabel and Sonja Loges",
note = "{\textcopyright} 2022. The Author(s).",
year = "2022",
month = dec,
day = "12",
doi = "10.1038/s41467-022-33938-x",
language = "English",
volume = "13",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

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

N1 - © 2022. The Author(s).

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.

KW - Mice

KW - Animals

KW - c-Mer Tyrosine Kinase/genetics

KW - Receptor Protein-Tyrosine Kinases/metabolism

KW - Proto-Oncogene Proteins/metabolism

KW - Homeostasis

KW - Carrier Proteins

U2 - 10.1038/s41467-022-33938-x

DO - 10.1038/s41467-022-33938-x

M3 - SCORING: Journal article

C2 - 36509738

VL - 13

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

M1 - 7689

ER -