Targeting Osteocytes Vs Osteoblasts

Overview

Journal Bone

Specialties Endocrinology
Orthopedics

Date 2023 Mar 3

PMID 36868508

Authors

Y Kitase

M Prideaux

Affiliations

Soon will be listed here.

Abstract

Although osteoblasts and osteocytes are descended from the same lineage, they each have unique and essential roles in bone. Targeting gene deletion to osteoblasts and osteocytes using the Cre/loxP system has greatly increased our current understanding of how these cells function. Additionally, the use of the Cre/loxP system in conjunction with cell-specific reporters has enabled lineage tracing of these bone cells both in vivo and ex vivo. However, concerns have been raised regarding the specificity of the promoters used and the resulting off-target effects on cells within and outside of the bone. In this review, we have summarized the main mouse models that have been used to determine the functions of specific genes in osteoblasts and osteocytes. We discuss the expression patterns and specificity of the different promoter fragments during osteoblast to osteocyte differentiation in vivo. We also highlight how their expression in non-skeletal tissues may complicate the interpretation of study results. A thorough understanding of when and where these promoters are activated will enable improved study design and greater confidence in data interpretation.

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References

Kalajzic I, Kalajzic Z, Kaliterna M, Gronowicz G, Clark S, Lichtler A . Use of type I collagen green fluorescent protein transgenes to identify subpopulations of cells at different stages of the osteoblast lineage. J Bone Miner Res. 2002; 17(1):15-25. DOI: 10.1359/jbmr.2002.17.1.15. View

Kretzschmar K, Post Y, Bannier-Helaouet M, Mattiotti A, Drost J, Basak O . Profiling proliferative cells and their progeny in damaged murine hearts. Proc Natl Acad Sci U S A. 2018; 115(52):E12245-E12254. PMC: 6310797. DOI: 10.1073/pnas.1805829115. View

Robling A, Niziolek P, Baldridge L, Condon K, Allen M, Alam I . Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2007; 283(9):5866-75. DOI: 10.1074/jbc.M705092200. View

Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng J, Behringer R . The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002; 108(1):17-29. DOI: 10.1016/s0092-8674(01)00622-5. View

Perry M, Gujra S, Whitworth T, Tobias J . Tamoxifen stimulates cancellous bone formation in long bones of female mice. Endocrinology. 2004; 146(3):1060-5. DOI: 10.1210/en.2004-1114. View

Liu F, Woitge H, Braut A, Kronenberg M, Lichtler A, Mina M . Expression and activity of osteoblast-targeted Cre recombinase transgenes in murine skeletal tissues. Int J Dev Biol. 2004; 48(7):645-53. DOI: 10.1387/ijdb.041816fl. View

Weng T, Huang J, Wagner E, Ko J, Wu M, Wareing N . Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation. J Exp Med. 2019; 217(2). PMC: 7041714. DOI: 10.1084/jem.20181384. View

Palumbo C . A three-dimensional ultrastructural study of osteoid-osteocytes in the tibia of chick embryos. Cell Tissue Res. 1986; 246(1):125-31. DOI: 10.1007/BF00219008. View

Ushiku C, Adams D, Jiang X, Wang L, Rowe D . Long bone fracture repair in mice harboring GFP reporters for cells within the osteoblastic lineage. J Orthop Res. 2010; 28(10):1338-47. DOI: 10.1002/jor.21105. View

10.

Indra A, Warot X, Brocard J, Bornert J, Xiao J, Chambon P . Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res. 1999; 27(22):4324-7. PMC: 148712. DOI: 10.1093/nar/27.22.4324. View

11.

Sheng M, Zhou X, Bonewald L, Baylink D, Lau K . Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice. Bone. 2012; 52(1):133-44. DOI: 10.1016/j.bone.2012.09.027. View

12.

Zhang M, Xuan S, Bouxsein M, von Stechow D, Akeno N, Faugere M . Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem. 2002; 277(46):44005-12. DOI: 10.1074/jbc.M208265200. View

13.

Toyosawa S, Shintani S, Fujiwara T, Ooshima T, Sato A, Ijuhin N . Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts. J Bone Miner Res. 2001; 16(11):2017-26. DOI: 10.1359/jbmr.2001.16.11.2017. View

14.

Sims N, White C, Sunn K, Thomas G, Drummond M, Morrison N . Human and murine osteocalcin gene expression: conserved tissue restricted expression and divergent responses to 1,25-dihydroxyvitamin D3 in vivo. Mol Endocrinol. 1997; 11(11):1695-708. DOI: 10.1210/mend.11.11.0008. View

15.

Clinkenbeard E, Cass T, Ni P, Hum J, Bellido T, Allen M . Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia. J Bone Miner Res. 2016; 31(6):1247-57. PMC: 4891276. DOI: 10.1002/jbmr.2792. View

16.

Kalajzic I, Braut A, Guo D, Jiang X, Kronenberg M, Mina M . Dentin matrix protein 1 expression during osteoblastic differentiation, generation of an osteocyte GFP-transgene. Bone. 2004; 35(1):74-82. DOI: 10.1016/j.bone.2004.03.006. View

17.

Zanotti S, Stadmeyer L, Smerdel-Ramoya A, Durant D, Canalis E . Misexpression of CCAAT/enhancer binding protein beta causes osteopenia. J Endocrinol. 2009; 201(2):263-74. PMC: 2674520. DOI: 10.1677/JOE-08-0514. View

18.

Ducy P, Karsenty G . Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene. Mol Cell Biol. 1995; 15(4):1858-69. PMC: 230411. DOI: 10.1128/MCB.15.4.1858. View

19.

Staines K, Javaheri B, Hohenstein P, Fleming R, Ikpegbu E, Unger E . Hypomorphic conditional deletion of E11/Podoplanin reveals a role in osteocyte dendrite elongation. J Cell Physiol. 2017; 232(11):3006-3019. PMC: 5575468. DOI: 10.1002/jcp.25999. View

20.

Xiong J, Onal M, Jilka R, Weinstein R, Manolagas S, OBrien C . Matrix-embedded cells control osteoclast formation. Nat Med. 2011; 17(10):1235-41. PMC: 3192296. DOI: 10.1038/nm.2448. View