Alendronate Affects Osteoblast Functions by Crosstalk Through EphrinB1-EphB

Overview

Journal J Dent Res

Specialty Dentistry

Date 2011 Dec 20

PMID 22180568

Citations 23

Authors

E Shimizu

J Tamasi

N C Partridge

Affiliations

Soon will be listed here.

Abstract

Bisphosphonates are therapeutic agents in the treatment of post-menopausal osteoporosis. Although they have been associated with delayed healing in injured tissues, inappropriate femoral fractures, and osteonecrosis of the jaw (ONJ), the pathophysiological mechanisms involved are not clear. Our hypothesis is that alendronate, a member of the N-containing bisphosphonates, indirectly inhibits osteoblast function through the coupling of osteoclasts to osteoblasts by ephrinB-EphB interaction. We found that alendronate increased gene and protein expression of ephrinB1 and EphB1, as well as B3, in femurs of adult mice injected with alendronate (10 µg/100 g/wk) for 8 weeks. Alendronate suppressed the expression of bone sialoprotein (BSP) and osteonectin in both femurs and bone marrow osteoblastic cells of mice. After elimination of pre-osteoclasts from bone marrow cells, alendronate did not affect osteoblast differentiation, indicating the need for pre-osteoclasts for alendronate's effects. Alendronate stimulated EphB1 and EphB3 protein expression in osteoblasts, whereas it enhanced ephrinB1 protein in pre-osteoclasts. In addition, a reverse signal by ephrinB1 inhibited osteoblast differentiation and suppressed BSP gene expression. Thus, alendronate, through its direct effects on the pre-osteoclast, appears to regulate expression of ephrinB1, which regulates and acts through the EphB1, B3 receptors on the osteoblast to suppress osteoblast differentiation.

Citing Articles

Alendronate treatment rescues the effects of compressive loading of TMJ in osteogenesis imperfecta mice.

Chen P, Mehta S, Dutra E, Yadav S Prog Orthod. 2024; 25(1):25.

PMID: 39004686 PMC: 11247069. DOI: 10.1186/s40510-024-00526-2.

Bioinspired core-shell nanofiber drug-delivery system modulates osteogenic and osteoclast activity for bone tissue regeneration.

Anjum S, Wang Y, Xin Y, Li X, Li T, Zhang H Mater Today Bio. 2024; 26:101088.

PMID: 38779556 PMC: 11109009. DOI: 10.1016/j.mtbio.2024.101088.

extracts stimulates bone healing in alveolar socket following tooth extraction.

Ayu Kartika I, Riani C, Insanu M, Adnyana I J Tradit Complement Med. 2022; 12(3):302-307.

PMID: 35493308 PMC: 9039093. DOI: 10.1016/j.jtcme.2021.08.010.

Mechanism, prevention, and treatment for medication-related osteonecrosis of the jaws.

Pan J, Liu J Hua Xi Kou Qiang Yi Xue Za Zhi. 2021; 39(3):245-254.

PMID: 34041871 PMC: 8218254. DOI: 10.7518/hxkq.2021.03.001.

Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment.

Arthur A, Gronthos S Front Cell Dev Biol. 2021; 9:598612.

PMID: 33634116 PMC: 7902060. DOI: 10.3389/fcell.2021.598612.

References

Huang R, Khan S, Sandhu H, Metzl J, Cammisa Jr F, Zheng F . Alendronate inhibits spine fusion in a rat model. Spine (Phila Pa 1976). 2005; 30(22):2516-22. DOI: 10.1097/01.brs.0000186470.28070.7b. View

Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T . Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. 2006; 4(2):111-21. DOI: 10.1016/j.cmet.2006.05.012. View

Hunter G, Goldberg H . Nucleation of hydroxyapatite by bone sialoprotein. Proc Natl Acad Sci U S A. 1993; 90(18):8562-5. PMC: 47397. DOI: 10.1073/pnas.90.18.8562. View

Pozzi S, Vallet S, Mukherjee S, Cirstea D, Vaghela N, Santo L . High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Clin Cancer Res. 2009; 15(18):5829-39. DOI: 10.1158/1078-0432.CCR-09-0426. View

Iwata K, Li J, Follet H, Phipps R, Burr D . Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia. Bone. 2006; 39(5):1053-1058. DOI: 10.1016/j.bone.2006.05.006. View

Xing W, Kim J, Wergedal J, Chen S, Mohan S . Ephrin B1 regulates bone marrow stromal cell differentiation and bone formation by influencing TAZ transactivation via complex formation with NHERF1. Mol Cell Biol. 2009; 30(3):711-21. PMC: 2812221. DOI: 10.1128/MCB.00610-09. View

Malaval L, Wade-Gueye N, Boudiffa M, Fei J, Zirngibl R, Chen F . Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis. J Exp Med. 2008; 205(5):1145-53. PMC: 2373846. DOI: 10.1084/jem.20071294. View

Chen J, SHAPIRO H, Sodek J . Development expression of bone sialoprotein mRNA in rat mineralized connective tissues. J Bone Miner Res. 1992; 7(8):987-97. DOI: 10.1002/jbmr.5650070816. View

Kubek D, Burr D, Allen M . Ovariectomy stimulates and bisphosphonates inhibit intracortical remodeling in the mouse mandible. Orthod Craniofac Res. 2010; 13(4):214-22. PMC: 3051277. DOI: 10.1111/j.1601-6343.2010.01497.x. View

10.

Zou J, Wang B, Kalo M, Zisch A, Pasquale E, Ruoslahti E . An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci U S A. 1999; 96(24):13813-8. PMC: 24147. DOI: 10.1073/pnas.96.24.13813. View

11.

Samadfam R, Xia Q, Goltzman D . Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice. J Bone Miner Res. 2006; 22(1):55-63. DOI: 10.1359/jbmr.060915. View

12.

Shimizu E, Selvamurugan N, Westendorf J, Olson E, Partridge N . HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression. J Biol Chem. 2010; 285(13):9616-9626. PMC: 2843211. DOI: 10.1074/jbc.M109.094862. View

13.

Orriss I, Key M, Colston K, Arnett T . Inhibition of osteoblast function in vitro by aminobisphosphonates. J Cell Biochem. 2008; 106(1):109-18. DOI: 10.1002/jcb.21983. View

14.

Van Beek E, Cohen L, Leroy I, Ebetino F, Lowik C, Papapoulos S . Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates. Bone. 2003; 33(5):805-11. DOI: 10.1016/j.bone.2003.07.007. View

15.

Valverde P, Tu Q, Chen J . BSP and RANKL induce osteoclastogenesis and bone resorption synergistically. J Bone Miner Res. 2005; 20(9):1669-79. DOI: 10.1359/JBMR.050511. View

16.

Fleisch H . Development of bisphosphonates. Breast Cancer Res. 2002; 4(1):30-4. PMC: 138713. DOI: 10.1186/bcr414. View

17.

Davy A, Bush J, Soriano P . Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol. 2006; 4(10):e315. PMC: 1563491. DOI: 10.1371/journal.pbio.0040315. View

18.

Davy A, Aubin J, Soriano P . Ephrin-B1 forward and reverse signaling are required during mouse development. Genes Dev. 2004; 18(5):572-83. PMC: 374238. DOI: 10.1101/gad.1171704. View

19.

Fisher L, Torchia D, Fohr B, Young M, Fedarko N . Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun. 2001; 280(2):460-5. DOI: 10.1006/bbrc.2000.4146. View

20.

Huja S, Fernandez S, Phillips C, Li Y . Zoledronic acid decreases bone formation without causing osteocyte death in mice. Arch Oral Biol. 2009; 54(9):851-6. DOI: 10.1016/j.archoralbio.2009.06.002. View