Regulation of bone homeostasis by MERTK and TYRO3

• Published in: Nature communications 2022-12, Vol.13 (1), p.7689-7689, Article 7689
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13; 13/106; 14; 14/34; 59; 59/5; 631/136/815/816; 631/154/555; 631/67/1344; 631/80/128/2031; 64; 64/60; Animals; Biological effects; Bone cancer; Bone diseases; Bone growth; Bone loss; Bone mass; Bone turnover; Breast cancer; c-Mer Tyrosine Kinase - genetics; c-Mer Tyrosine Kinase - metabolism; Cancer; Carrier Proteins; Contractility; Gene deletion; Homeostasis; Humanities and Social Sciences; Kinases; Lung cancer; Metastases; Metastasis; Mice; multidisciplinary; Multiple myeloma; Osteoblastogenesis; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Phenotypes; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptors; RhoA protein; Science; Science (multidisciplinary); Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33938-x

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. The TAM family of receptor tyrosine kinases exerts pleiotropic functions in health and disease. Here, the authors show that TAM receptors control osteoblastic bone formation and identified MERTK as a novel target for bone anabolic therapy and mitigation of bone metastasis including its associated osteolytic bone disease