The G60S connexin 43 mutation activates the osteoblast lineage and results in a resorption-stimulating bone matrix and abrogation of old-age-related bone loss

Journal of Bone and Mineral Research

Volumn 28, Issue 11, 2013, Pages 2400-2413

  Zappitelli, Tanya ^a   Chen, Frieda ^a   Moreno, Luisa ^a   Zirngibl, Ralph A ^a   Grynpas, Marc ^a,b   Henderson, Janet E ^c   Aubin, Jane E ^a,b  

^a UNIVERSITY OF TORONTO   (Canada)

^b MOUNT SINAI HOSPITAL   (Canada)

^c MONTREAL GENERAL HOSPITAL   (Canada)

Author keywords

AGE RELATED BONE LOSS; BONE SIALOPROTEIN; CONNEXIN 43; OSTEOPENIA; RANKL OPG SIGNALING

Indexed keywords

ACID PHOSPHATASE TARTRATE RESISTANT ISOENZYME; ALKALINE PHOSPHATASE; BONE SIALOPROTEIN; CALCITONIN RECEPTOR; CATHEPSIN K; COLLAGEN; COLLAGEN 1A1; CONNEXIN 43; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; TRANSCRIPTION FACTOR NFAT; TRANSCRIPTION FACTOR OSTERIX; TRANSCRIPTION FACTOR RUNX2; UNCLASSIFIED DRUG;

ALKALINE PHOSPHATASE BLOOD LEVEL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BONE DENSITY; BONE MASS; BONE MATRIX; CELL DIFFERENTIATION; CELL LINEAGE; CELL PROLIFERATION; CONTROLLED STUDY; FEMALE; GENE EXPRESSION; GENE MUTATION; GENOTYPE; IN VITRO STUDY; IN VIVO STUDY; LONGITUDINAL STUDY; MALE; MOUSE; NONHUMAN; OSTEOBLAST; OSTEOCLAST; OSTEOCLAST ACTIVITY; OSTEOCLASTOGENESIS; OSTEOLYSIS; OSTEOPENIA; TRABECULAR BONE; UPREGULATION;

AGE-RELATED BONE LOSS; BONE SIALOPROTEIN; CONNEXIN 43; OSTEOPENIA; RANKL-OPG SIGNALING;

ANIMALS; BIOMECHANICAL PHENOMENA; BONE DENSITY; BONE MATRIX; BONE RESORPTION; CELL COUNT; CELL LINEAGE; CONNEXIN 43; FEMALE; FEMUR; INTEGRIN-BINDING SIALOPROTEIN; MALE; MICE; MICE, INBRED C57BL; MUTATION; OSTEOBLASTS; OSTEOPROTEGERIN; RANK LIGAND;

EID: 84886811033     PISSN: 08840431     EISSN: 15234681     Source Type: Journal    
DOI: 10.1002/jbmr.1965     Document Type: Article

References (42)

1. Civitelli R, Beyer EC, Warlow PM, Robertson AJ, Geist ST, Steinberg TH., Connexin43 mediates direct intercellular communication in human osteoblastic cell networks. J Clin Invest. 1993; 91: 1888-96.
2. Mason DJ, Hillam RA, Skerry TM., Constitutive in vivo mRNA expression by osteocytes of beta-actin, osteocalcin, connexin-43, IGF-I, c-fos and c-jun, but not TNF-alpha nor tartrate-resistant acid phosphatase. J Bone Miner Res. 1996; 11: 350-7.
3. Jones SJ, Gray C, Sakamaki H, Arora M, Boyde A, Gourdie R, Green C., The incidence and size of gap junctions between the bone cells in rat calvaria. Anat Embryol (Berl). 1993; 187: 343-52.
4. Zhang Y, Paul EM, Sathyendra V, Davison A, Sharkey N, Bronson S, Srinivasan S, Gross TS, Donahue HJ., Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone. PLoS One. 2011; 6: e23516.
5. Lecanda F, Warlow PM, Sheikh S, Furlan F, Steinberg TH, Civitelli R., Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol. 2000; 151: 931-44.
6. Chung DJ, Castro CH, Watkins M, Stains JP, Chung MY, Szejnfeld VL, Willecke K, Theis M, Civitelli R., Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43. J Cell Sci. 2006; 119: 4187-98.
7. Watkins M, Grimston SK, Norris JY, Guillotin B, Shaw A, Beniash E, Civitelli R., Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Mol Biol Cell. 2011; 22: 1240-51.
8. Bivi N, Condon KW, Allen MR, Farlow N, Passeri G, Brun LR, Rhee Y, Bellido T, Plotkin LI., Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res. 2012; 27: 374-89.
9. Bivi N, Nelson MT, Faillace ME, Li J, Miller LM, Plotkin LI., Deletion of Cx43 from osteocytes results in defective bone material properties but does not decrease extrinsic strength in cortical bone. Calcif Tissue Int. 2012; 91: 215-24.
10. Plotkin LI, Lezcano V, Thostenson J, Weinstein RS, Manolagas SC, Bellido T., Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J Bone Miner Res. 2008; 23: 1712-21.
11. Lloyd SA, Lewis GS, Zhang Y, Paul EM, Donahue HJ., Connexin 43 deficiency attenuates loss of trabecular bone and prevents suppression of cortical bone formation during unloading. J Bone Miner Res. 2012; 27: 2359-72.
12. Grimston SK, Watkins MP, Brodt MD, Silva MJ, Civitelli R., Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice. PLoS One. 2012; 7: e44222.
13. Dobrowolski R, Sasse P, Schrickel JW, Watkins M, Kim JS, Rackauskas M, Troatz C, Ghanem A, Tiemann K, Degen J, Bukauskas FF, Civitelli R, Lewalter T, Fleischmann BK, Willecke K., The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans. Hum Mol Genet. 2008; 17: 539-54.
14. Flenniken AM, Osborne LR, Anderson N, Ciliberti N, Fleming C, Gittens JE, Gong XQ, Kelsey LB, Lounsbury C, Moreno L, Nieman BJ, Peterson K, Qu D, Roscoe W, Shao Q, Tong D, Veitch GI, Voronina I, Vukobradovic I, Wood GA, Zhu Y, Zirngibl RA, Aubin JE, Bai D, Bruneau BG, Grynpas M, Henderson JE, Henkelman RM, McKerlie C, Sled JG, Stanford WL, Laird DW, Kidder GM, Adamson SL, Rossant J., A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Development. 2005; 132: 4375-86.
15. Gladwin A, Donnai D, Metcalfe K, Schrander-Stumpel C, Brueton L, Verloes A, Aylsworth A, Toriello H, Winter R, Dixon M., Localization of a gene for oculodentodigital syndrome to human chromosome 6q22-q24. Hum Mol Genet. 1997; 6: 123-7.
16. McLachlan E, Plante I, Shao Q, Tong D, Kidder GM, Bernier SM, Laird DW., ODDD-linked Cx43 mutants reduce endogenous Cx43 expression and function in osteoblasts and inhibit late stage differentiation. J Bone Miner Res. 2008; 23: 928-38.
17. Valverde-Franco G, Liu H, Davidson D, Chai S, Valderrama-Carvajal H, Goltzman D, Ornitz DM, Henderson JE., Defective bone mineralization and osteopenia in young adult FGFR3-/- mice. Hum Mol Genet. 2004; 13: 271-84.
18. Sardone LD, Renlund R, Willett TL, Fantus IG, Grynpas MD., Effect of rosiglitazone on bone quality in a rat model of insulin resistance and osteoporosis. Diabetes. 2011; 60: 3271-8.
19. Carson FL., Histotechnology: a self-instructional text. Chicago: American Society for Clinical Pathology Press; 1990; p. 294.
20. Wang X, Seed B., A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res. 2003; 31: e154.
21. Zhao S, Fernald RD., Comprehensive algorithm for quantitative real-time polymerase chain reaction. J Comput Biol. 2005; 12: 1047-64.
22. Scutt A, Beier N, Fittschen C., EMD273316 & EMD95833, type 4 phosphodiesterase inhibitors, stimulate fibroblastic-colony formation by bone marrow cells via direct inhibition of PDE4 and the induction of endogenous prostaglandin synthesis. BMC Pharmacol. 2004; 4: 10.
23. Bellows CG, Aubin JE, Heersche JN, Antosz ME., Mineralized bone nodules formed in vitro from enzymatically released rat calvaria cell populations. Calcif Tissue Int. 1986; 38: 143-54.
24. Goldberg HA, Sodek J., Purification of mineralized tissue-associated osteopontin. Methods Cell Sci. 1994; 16: 211-5.
25. Thomas T, Telford D, Laird DW., Functional domain mapping and selective trans-dominant effects exhibited by Cx26 disease-causing mutations. J Biol Chem. 2004; 279: 19157-68.
26. Malaval L, Wade-Gueye NM, Boudiffa M, Fei J, Zirngibl R, Chen F, Laroche N, Roux JP, Burt-Pichat B, Duboeuf F, Boivin G, Jurdic P, Lafage-Proust MH, Amedee J, Vico L, Rossant J, Aubin JE., Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis. J Exp Med. 2008; 205: 1145-53.
27. Gonzalez-Nieto D, Li L, Kohler A, Ghiaur G, Ishikawa E, Sengupta A, Madhu M, Arnett J, Santho R, Dunn SK, Fishman GI, Gutstein DE, Civitelli R, Barrio LC, Gunzer M, Cancelas JA., Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood. 2012 May 31; 119 (22): 5144-54.
28. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C., Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008; 23: 860-9.
29. Liu F, Malaval L, Aubin JE., Global amplification polymerase chain reaction reveals novel transitional stages during osteoprogenitor differentiation. J Cell Sci. 2003; 116: 1787-96.
30. Wilson SE, Mohan RR, Netto M, Perez V, Possin D, Huang J, Kwon R, Alekseev A, Rodriguez-Perez JP., RANK, RANKL, OPG, and M-CSF expression in stromal cells during corneal wound healing. Invest Ophthalmol Vis Sci. 2004; 45: 2201-11.
31. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM., Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999; 402: 304-9.
32. Valverde P, Tu Q, Chen J., BSP and RANKL induce osteoclastogenesis and bone resorption synergistically. J Bone Miner Res. 2005; 20: 1669-79.
33. Valverde P, Zhang J, Fix A, Zhu J, Ma W, Tu Q, Chen J., Overexpression of bone sialoprotein leads to an uncoupling of bone formation and bone resorption in mice. J Bone Miner Res. 2008; 23: 1775-88.
34. Grimston SK, Brodt MD, Silva MJ, Civitelli R., Attenuated response to in vivo mechanical loading in mice with conditional osteoblast ablation of the connexin43 gene (Gja1). J Bone Miner Res. 2008; 23: 879-86.
35. Asumda FZ, Chase PB., Age-related changes in rat bone-marrow mesenchymal stem cell plasticity. BMC Cell Biol. 2011; 12: 44.
36. Genetos DC, Zhou Z, Li Z, Donahue HJ., Age-related changes in gap junctional intercellular communication in osteoblastic cells. J Orthop Res. 2012; 30: 1979-84.
37. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L., A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997; 390: 175-9.
38. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS 3rd, Frankel WN, Lee SY, Choi Y., TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997; 272: 25190-4.
39. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T., Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998; 95: 3597-602.
40. Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K., Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998; 139: 1329-37.
41. Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K., Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun. 1997; 234: 137-42.
42. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ., Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89: 309-19.