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© The Rockefeller University Press, 0021-9525/2000//931 $5.00
The Journal of Cell Biology, Volume 151, Number 4, , 2000 931-944

Connexin43 Deficiency Causes Delayed Ossification, Craniofacial Abnormalities, and Osteoblast Dysfunction

^a Divisions of Bone and Mineral and Infectious Diseases, Department of Internal Medicine
^b Department of Cell Biology and Physiology, Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri 63110
Division of Bone and Mineral Diseases, Barnes-Jewish Hospital of St. Louis, Mailstop: 90-32-656, 216 S. Kingshighway Blvd., St. Louis, MO 63110.(314) 454-5047(314) 454-7765

Connexin(Cx)43 is the major gap junction protein present in osteoblasts. We have shown that overexpression of Cx45 in osteoblasts expressing endogenous Cx43 leads to decreased cell–cell communication (Koval, M., S.T. Geist, E.M. Westphale, A.E. Kemendy, R. Civitelli, E.C. Beyer, and T.H. Steinberg. 1995. J. Cell Biol. 130:987–995) and transcriptional downregulation of several osteoblastic differentiation markers (Lecanda, F., D.A. Towler, K. Ziambaras, S.-L. Cheng, M. Koval, T.H. Steinberg, and R. Civitelli. 1998. Mol. Biol. Cell 9:2249–2258). Here, using the Cx43-null mouse model, we determined whether genetic deficiency of Cx43 affects skeletal development in vivo. Both intramembranous and endochondral ossification of the cranial vault were delayed in the mutant embryos, and cranial bones originating from migratory neural crest cells were also hypoplastic, leaving an open foramen at birth. Cx43-deficient animals also exhibited retarded ossification of the clavicles, ribs, vertebrae, and limbs, demonstrating that skeletal abnormalities are not restricted to a neural crest defect. However, the axial and appendicular skeleton of Cx43-null animals were essentially normal at birth. Cell to cell diffusion of calcein was poor among Cx43-deficient osteoblasts, whose differentiated phenotypic profile and mineralization potential were greatly impaired, compared with wild-type cells. Therefore, in addition to the reported neural crest cell defect, lack of Cx43 also causes a generalized osteoblast dysfunction, leading to delayed mineralization and skull abnormalities. Cell to cell signaling, mediated by Cx43 gap junctions, was critical for normal osteogenesis, craniofacial development, and osteoblastic function.

Key Words: connexin43 • connexin45 • gene knockout • skeletal development • osteoblast differentiation

© 2000 The Rockefeller University Press

This work was partially presented in abstract form at the 20th and 21st annual meetings of the American Society for Bone and Mineral Research, San Francisco, CA, December 1998, Abstract S149; and St. Louis, MO, October 1999, Abstract S173.

Abbreviations used in this paper: Cx, connexin; E, embryonic day; RT, reverse transcriptase.

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