Browsing by Author "Reginato, Rejane D."

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    Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain
    (Elsevier, 2015-12) Pacheco-Costa, Rafael; Davis, Hannah M.; Sorenson, Chad; Hon, Mary C.; Hassan, Iraj; Reginato, Rejane D.; Allen, Matthew R.; Bellido, Teresita; Plotkin, Lilian I.; Department of Anatomy & Cell Biology, IU School of Medicine
    Connexin 43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. To determine the role of Cx43 CT domain in bone, mice in which one allele of full length Cx43 was replaced by a mutant lacking the CT domain (Cx43(ΔCT/fl)) were studied. Cx43(ΔCT/fl) mice exhibit lower cancellous bone volume but higher cortical thickness than Cx43(fl/fl) controls, indicating that the CT domain is involved in normal cancellous bone gain but opposes cortical bone acquisition. Further, Cx43(ΔCT) is able to exert the functions of full length osteocytic Cx43 on cortical bone geometry and mechanical properties, demonstrating that domains other than the CT are responsible for Cx43 function in cortical bone. In addition, parathyroid hormone (PTH) failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture, in cortical bone in Cx43(ΔCT) mice with or without osteocytic full length Cx43. On the other hand, bone mass and bone formation markers were increased by the hormone in all mouse models, regardless of whether full length or Cx43(ΔCT) were or not expressed. We conclude that Cx43 CT domain is involved in proper bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions.
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    High Bone Mass in Mice Lacking Cx37 Due to Defective Osteoclast Differentiation
    (American Society for Biochemistry and Molecular Biology, 2014-02) Pacheco-Costa, Rafael; Hassan, Iraj; Reginato, Rejane D.; Davis, Hannah M.; Bruzzaniti, Angela; Allen, Matthew R.; Plotkin, Lilian I.; Department of Anatomy & Cell Biology, School of Medicine
    Connexin (Cx) proteins are essential for cell differentiation, function and survival in all tissues with Cx43 being the most studied in bone. We now report that Cx37, another member of the connexin family of proteins, is expressed in osteoclasts, osteoblasts and osteocytes. Mice with global deletion of Cx37 (Cx37-/-) exhibit higher BMD, cancellous bone volume, and mechanical strength compared to wild type littermates. Osteoclast number and surface are significantly lower in bone of Cx37-/- mice. In contrast, osteoblast number and surface and bone formation rate in bones from Cx37-/- mice are unchanged. Moreover, markers of osteoblast activity ex vivo and in vivo are similar to those of Cx37+/+ littermates. sRANKL/M-CSF treatment of non-adherent Cx37-/- bone marrow cells rendered a 5-fold lower level of osteoclast differentiation compared to Cx37+/+ cell cultures. Further, Cx37-/- osteoclasts are smaller and have fewer nuclei per cell. Expression of RANK, TRAP, cathepsin K, calcitonin receptor, MMP9, NFATc1, DCSTAMP, ATP6v0d1 and CD44, markers of osteoclast number, fusion or activity, is lower in Cx37-/- osteoclasts compared to controls. In addition, non-adherent bone marrow cells from Cx37-/- mice exhibit higher levels of markers for osteoclast precursors, suggesting altered osteoclast differentiation. The reduction of osteoclast differentiation is associated with activation of Notch signaling. We conclude that Cx37 is required for osteoclast differentiation and fusion and its absence leads to arrested osteoclast maturation and high bone mass in mice. These findings demonstrate a previously unrecognized role of Cx37 in bone homeostasis that is not compensated for by Cx43 in vivo.