4.8 Article

Regulation of bone homeostasis by MERTK and TYRO3

期刊

NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

出版社

NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33938-x

关键词

-

资金

  1. DFG [LO1863/5-1, BE6658/2-1]
  2. University Cancer Center Hamburg (UCCH)
  3. Heisenberg professorship (DFG)
  4. European Research Council (ERC) under the European Union [758713]
  5. Hector Stiftung II
  6. German Research Foundation [SPP 2084, HE 5208/5-1, TA 1154/2-1, TA 1154/1-1, TA 1154/1-2]
  7. Projekt DEAL
  8. European Research Council (ERC) [758713] Funding Source: European Research Council (ERC)

向作者/读者索取更多资源

This study demonstrates the reciprocal effects of TAM receptors MERTK and TYRO3 in maintaining the balance of bone homeostasis. Blocking MERTK can increase osteoblast numbers and promote bone formation, consequently reducing cancer-induced bone loss and improving survival.
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

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据