Regulation of bone homeostasis by MERTK and TYRO3.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 12 2022
12 12 2022
Historique:
received:
29
04
2021
accepted:
07
10
2022
entrez:
12
12
2022
pubmed:
13
12
2022
medline:
15
12
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36509738
doi: 10.1038/s41467-022-33938-x
pii: 10.1038/s41467-022-33938-x
pmc: PMC9744875
doi:
Substances chimiques
c-Mer Tyrosine Kinase
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Proto-Oncogene Proteins
0
Carrier Proteins
0
Mertk protein, mouse
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7689Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Sims, N. A. & Martin, T. J. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep. 3, 481 (2014).
doi: 10.1038/bonekey.2013.215
Rutkovskiy, A., Stenslokken, K. O. & Vaage, I. J. Osteoblast differentiation at a glance. Med. Sci. Monit. Basic Res. 22, 95–106 (2016).
doi: 10.12659/MSMBR.901142
Baron, R. & Kneissel, M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179–192 (2013).
doi: 10.1038/nm.3074
McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412–420 (2014).
doi: 10.1056/NEJMoa1305224
Solling, A. S. K., Harslof, T. & Langdahl, B. The clinical potential of romosozumab for the prevention of fractures in postmenopausal women with osteoporosis. Ther. Adv. Musculoskelet. Dis. 10, 105–115 (2018).
doi: 10.1177/1759720X18775936
Saag, K. G. et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N. Engl. J. Med. 377, 1417–1427 (2017).
doi: 10.1056/NEJMoa1708322
Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).
doi: 10.1038/nature17630
Bosurgi, L. et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 356, 1072–1076 (2017).
doi: 10.1126/science.aai8132
Chan, P. Y. et al. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352, 99–103 (2016).
doi: 10.1126/science.aaf1358
Prasad, D. et al. TAM receptor function in the retinal pigment epithelium. Mol. Cell Neurosci. 33, 96–108 (2006).
doi: 10.1016/j.mcn.2006.06.011
Zagorska, A. et al. Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer. Life Sci Alliance 3, e202000694 (2020).
Rothlin, C. V., Carrera-Silva, E. A., Bosurgi, L. & Ghosh, S. TAM receptor signaling in immune homeostasis. Annu. Rev. Immunol. 33, 355–391 (2015).
doi: 10.1146/annurev-immunol-032414-112103
Tondo, G., Perani, D. & Comi, C. TAM receptor pathways at the crossroads of neuroinflammation and neurodegeneration. Dis. Markers 2019, 2387614 (2019).
doi: 10.1155/2019/2387614
Ruiz-Heiland, G. et al. Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis. Ann. Rheum. Dis. 73, 771–779 (2014).
doi: 10.1136/annrheumdis-2012-202907
Graham, D. K., DeRyckere, D., Davies, K. D. & Earp, H. S. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer 14, 769–785 (2014).
doi: 10.1038/nrc3847
Gadiyar, V., Patel, G. & Davra, V. Immunological role of TAM receptors in the cancer microenvironment. Int. Rev. Cell Mol. Biol. 357, 57–79 (2020).
doi: 10.1016/bs.ircmb.2020.09.011
David Roodman, G. & Silbermann, R. Mechanisms of osteolytic and osteoblastic skeletal lesions. Bonekey Rep. 4, 753 (2015).
doi: 10.1038/bonekey.2015.122
Coleman, R. E. et al. Metastasis and bone loss: advancing treatment and prevention. Cancer Treat. Rev. 36, 615–620 (2010).
doi: 10.1016/j.ctrv.2010.04.003
Kolb, A. D., Shupp, A. B., Mukhopadhyay, D., Marini, F. C. & Bussard, K. M. Osteoblasts are “educated” by crosstalk with metastatic breast cancer cells in the bone tumor microenvironment. Breast Cancer Res. 21, 31 (2019).
doi: 10.1186/s13058-019-1117-0
Hesse, E. et al. Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI Insight 5, e125543 (2019).
Paton-Hough, J. et al. Preventing and repairing myeloma bone disease by combining conventional antiresorptive treatment with a bone anabolic agent in murine models. J. Bone Min. Res. 34, 783–796 (2019).
doi: 10.1002/jbmr.3606
Chen, Y. C., Sosnoski, D. M. & Mastro, A. M. Breast cancer metastasis to the bone: mechanisms of bone loss. Breast Cancer Res. 12, 215 (2010).
Dacquin, R., Starbuck, M., Schinke, T. & Karsenty, G. Mouse alpha1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast. Dev. Dyn. 224, 245–251 (2002).
doi: 10.1002/dvdy.10100
Wang, M. et al. Smad1 plays an essential role in bone development and postnatal bone formation. Osteoarthr. Cartil. 19, 751–762 (2011).
doi: 10.1016/j.joca.2011.03.004
Lee, Y. J., Park, H. J., Woo, S. Y., Park, E. M. & Kang, J. L. RhoA/phosphatidylinositol 3-kinase/protein kinase B/mitogen-activated protein kinase signaling after growth arrest-specific protein 6/mer receptor tyrosine kinase engagement promotes epithelial cell growth and wound repair via upregulation of hepatocyte growth factor in macrophages. J. Pharm. Exp. Ther. 350, 563–577 (2014).
doi: 10.1124/jpet.114.215673
Negishi-Koga, T. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med. 17, 1473–1480 (2011).
doi: 10.1038/nm.2489
Svitkina, T. The actin cytoskeleton and actin-based motility. Cold Spring Harb. Perspect. Biol. 10, a018267 (2018).
Zouani, O. F., Rami, L., Lei, Y. & Durrieu, M. C. Insights into the osteoblast precursor differentiation towards mature osteoblasts induced by continuous BMP-2 signaling. Biol. Open 2, 872–881 (2013).
doi: 10.1242/bio.20134986
Tojkander, S., Gateva, G. & Lappalainen, P. Actin stress fibers–assembly, dynamics and biological roles. J. Cell Sci. 125, 1855–1864 (2012).
Vicente-Manzanares, M., Ma, X., Adelstein, R. S. & Horwitz, A. R. Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat. Rev. Mol. Cell Biol. 10, 778–790 (2009).
doi: 10.1038/nrm2786
Mahajan, N. P. & Earp, H. S. An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action. J. Biol. Chem. 278, 42596–42603 (2003).
doi: 10.1074/jbc.M305817200
Shelby, S. J., Colwill, K., Dhe-Paganon, S., Pawson, T. & Thompson, D. A. MERTK interactions with SH2-domain proteins in the retinal pigment epithelium. PLoS ONE 8, e53964 (2013).
doi: 10.1371/journal.pone.0053964
Faccio, R. et al. Vav3 regulates osteoclast function and bone mass. Nat. Med. 11, 284–290 (2005).
doi: 10.1038/nm1194
Jannie, K. M. et al. Vinculin-dependent actin bundling regulates cell migration and traction forces. Biochem. J. 465, 383–393 (2015).
doi: 10.1042/BJ20140872
Vallenius, T. Actin stress fibre subtypes in mesenchymal-migrating cells. Open Biol. 3, 130001 (2013).
doi: 10.1098/rsob.130001
O’Donnell, E. K. & Raje, N. S. Myeloma bone disease: pathogenesis and treatment. Clin. Adv. Hematol. Oncol. 15, 285–295 (2017).
Brook, N., Brook, E., Dharmarajan, A., Dass, C. R. & Chan, A. Breast cancer bone metastases: pathogenesis and therapeutic targets. Int. J. Biochem. Cell Biol. 96, 63–78 (2018).
doi: 10.1016/j.biocel.2018.01.003
Rossi, A., Gridelli, C., Ricciardi, S. & de Marinis, F. Bone metastases and non-small cell lung cancer: from bisphosphonates to targeted therapy. Curr. Med. Chem. 19, 5524–5535 (2012).
doi: 10.2174/092986712803833209
Ubil, E. et al. Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. J. Clin. Investig. 128, 2356–2369 (2018).
doi: 10.1172/JCI97354
Che Mat, M. F. et al. Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells. Int. J. Oncol. 49, 2359–2366 (2016).
doi: 10.3892/ijo.2016.3755
Saraon, P. et al. Proteomic profiling of androgen-independent prostate cancer cell lines reveals a role for protein S during the development of high grade and castration-resistant prostate cancer. J. Biol. Chem. 287, 34019–34031 (2012).
doi: 10.1074/jbc.M112.384438
Xie, S. et al. Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib. Oncotarget 6, 9206–9219 (2015).
doi: 10.18632/oncotarget.3280
Waizenegger, J. S. et al. Role of growth arrest-specific gene 6-Mer axis in multiple myeloma. Leukemia 29, 696–704 (2015).
doi: 10.1038/leu.2014.236
Linger, R. M., Keating, A. K., Earp, H. S. & Graham, D. K. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors. Expert Opin. Ther. Targets 14, 1073–1090 (2010).
doi: 10.1517/14728222.2010.515980
Smart, S. K., Vasileiadi, E., Wang, X., DeRyckere, D. & Graham, D. K. The emerging role of TYRO3 as a therapeutic target in cancer. Cancers 10, 474.(2018).
Krishnan, V., Dhurjati, R., Vogler, E. A. & Mastro, A. M. Osteogenesis in vitro: from pre-osteoblasts to osteocytes: a contribution from the Osteobiology Research Group, The Pennsylvania State University. Vitr. Cell Dev. Biol. Anim. 46, 28–35 (2010).
doi: 10.1007/s11626-009-9238-x
Tang, Y. et al. Mertk deficiency affects macrophage directional migration via disruption of cytoskeletal organization. PLoS ONE 10, e0117787 (2015).
doi: 10.1371/journal.pone.0117787
Lemke, G. & Rothlin, C. V. Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8, 327–336 (2008).
doi: 10.1038/nri2303
Burstyn-Cohen, T., Heeb, M. J. & Lemke, G. Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J. Clin. Invest. 119, 2942–2953 (2009).
doi: 10.1172/JCI39325
Seeman, E. & Martin, T. J. Antiresorptive and anabolic agents in the prevention and reversal of bone fragility. Nat. Rev. Rheumatol. 15, 225–236 (2019).
doi: 10.1038/s41584-019-0172-3
Holland, S. J. et. al. Small molecule inhibitors of the anti-inflammatory TAM receptor MerTK. [abstract]. Cancer Res. 76, 4869 (2016).
Kristinsson, S. Y., Minter, A. R., Korde, N., Tan, E. & Landgren, O. Bone disease in multiple myeloma and precursor disease: novel diagnostic approaches and implications on clinical management. Expert Rev. Mol. Diagn. 11, 593–603 (2011).
doi: 10.1586/erm.11.44
Weber, K., Mock, U., Petrowitz, B., Bartsch, U. & Fehse, B. Lentiviral gene ontology (LeGO) vectors equipped with novel drug-selectable fluorescent proteins: new building blocks for cell marking and multi-gene analysis. Gene Ther. 17, 511–520 (2010).
doi: 10.1038/gt.2009.149
Weber, K., Bartsch, U., Stocking, C. & Fehse, B. A multicolor panel of novel lentiviral “gene ontology” (LeGO) vectors for functional gene analysis. Mol. Ther. 16, 698–706 (2008).
doi: 10.1038/mt.2008.6
Lineham, E., Tizzard, G. J., Coles, S. J., Spencer, J. & Morley, S. J. Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells. Oncotarget 9, 14148–14159 (2018).
doi: 10.18632/oncotarget.24354
Bouxsein, M. L. et al. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J. Bone Min. Res. 25, 1468–1486 (2010).
doi: 10.1002/jbmr.141