Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Nat Commun. 2022 Dec 12;13(1):7689. 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.
破骨细胞和成骨细胞精细平衡地维持着骨内稳态。在这里，我们发现 TAM 受体 MERTK 和 TYRO3 在成骨细胞生物学中发挥相互作用：成骨细胞靶向敲除 MERTK 可促进健康小鼠和癌症诱导性骨丢失小鼠的骨量增加，而敲除成骨细胞中的 TYRO3 则表现出相反的表型。功能上，MERTK 与其配体 PROS1 的相互作用通过诱导 VAV2-RHOA-ROCK 轴负向调节成骨细胞分化，导致细胞收缩力和迁移性增加，而 TYRO3 拮抗这种作用。因此，小分子抑制剂 R992 对 MERTK 的药理学阻断可增加小鼠的成骨细胞数量和骨形成。此外，R992 可对抗癌症引起的骨丢失，减少骨转移，并延长多发性骨髓瘤、乳腺癌和肺癌的临床前模型中的生存期。总之，MERTK 和 TYRO3 是骨内稳态的有效调节因子，具有细胞类型特异性功能，MERTK 阻断代表一种具有成骨活性的治疗方法，其应用不仅限于癌症。
