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Nmp4/CIZ Suppresses the Response of Bone to Anabolic Parathyroid Hormone by Regulating Both Osteoblasts and Osteoclasts

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Abstract

How parathyroid hormone (PTH) increases bone mass is unclear, but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth, we treated 10-week-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH(1–34) at 30 μg/kg daily or vehicle, 7 days/week, for 2, 3, or 7 weeks. Null mice treated with hormone (7 weeks) gained more vertebral and tibial cancellous bone than WT animals, paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 weeks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone, these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 weeks into treatment. Unexpectedly, the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptide, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts was elevated in Nmp4-KO mice at 2 weeks, but not 3 weeks, of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity and number of both osteoblasts and osteoclasts.

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Acknowledgments

This work was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, NIH), grant DK053796 (to J. P. B.).

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Author notes

  1. Binu K. Philip

    Present address: Bristol-Myers Squibb, Mt. Vernon, IN, 47620, USA

  2. Aaron Heller

    Present address: Kansas City University of Medicine and Biosciences, Kansas City, MO, 64106-1453, USA

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Indiana University School of Medicine (IUSM), Medical Science Bldg. 5035, 635 Barnhill Drive, Indianapolis, IN, 46202, USA

    Paul Childress, Binu K. Philip, Alexander G. Robling, Melissa A. Kacena, Nicoletta Bivi, Lilian I. Plotkin, Aaron Heller & Joseph P. Bidwell

  2. Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, IN, 46202, USA

    Alexander G. Robling & Melissa A. Kacena

  3. Department of Oral Biology, Indiana University School of Dentistry, Indianapolis, IN, USA

    Angela Bruzzaniti

  4. Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

    Melissa A. Kacena

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  1. Paul Childress
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Correspondence to Joseph P. Bidwell.

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Childress, P., Philip, B.K., Robling, A.G. et al. Nmp4/CIZ Suppresses the Response of Bone to Anabolic Parathyroid Hormone by Regulating Both Osteoblasts and Osteoclasts. Calcif Tissue Int 89, 74–89 (2011). https://doi.org/10.1007/s00223-011-9496-y

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