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Monthly Administration of a Novel PTH-Collagen Binding Domain Fusion Protein is Anabolic in Mice

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Abstract

We synthesized fusion proteins of parathyroid hormone (PTH) (1–33) and the collagen binding domain of ColH (CBD) and tested them for anabolic bone activity in mice. Two fusion proteins were synthesized, linking the carboxy terminus of PTH(1–33) either directly to the amino terminal of the CBD or to the CBD through an adjacent ColH domain (PTH-PKD-CBD). Both PTH-CBD and PTH-PKD-CBD increased cAMP accumulation in cells stably transfected with the PTH/PTHrP receptor, and both peptides bound to type 1 collagen in flow-through assays. Distribution studies indicated that the PTH-CBD was concentrated in the bone and skin, tissues with abundant collagen and blood flow. Administration of 320 μg/kg PTH-CBD either weekly (for 8 weeks) or monthly (for 6 months) to 7-week-old C57BL/6J mice resulted in a sustained increase in bone mineral density (BMD) (15% for weekly studies, 13% for monthly studies; P < 0.05). PTH-PKD-CBD showed only 5% increases in BMD after weekly administration, and, as expected, neither weekly nor monthly PTH(1–34) affected BMD. PTH-CBD increased serum alkaline phosphatase levels. Importantly, there were no significant increases in serum calcium observed. Collectively, the data suggest that PTH-CBD has a sustained anabolic effect in bone with either weekly or monthly administration. This approach of targeted delivery of PTH to bone may show promise for the treatment of disorders of low bone mass, such as postmenopausal osteoporosis.

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Acknowledgment

We thank Ochsner Clinic Foundation for providing support for these studies. We also thank Dr. Alan Burshell (Chief Endocrinology Department, Ochsner Clinic Foundation, New Orleans, LA) for help, support, and encouragement. O. M. is supported by a Grant-in Aid for Scientific Research (C) from the Japan Society for the Promotion of Science. We thank Dr. Thomas Gardella (Endocrine Unit, Massachusetts General Hospital, Boston, MA) for kindly providing the cells used in these studies.

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Authors and Affiliations

  1. Pediatric Endocrinology, Children’s Hospital at Montefiore, 3415 Bainbridge Avenue, Bronx, 10467, Bronx, NY, USA

    Tulasi Ponnapakkam, R. Katikaneni & R. C. Gensure

  2. Albert Einstein College of Medicine, Bronx, NY, USA

    Tulasi Ponnapakkam, R. Katikaneni & R. C. Gensure

  3. Pediatric Endocrinology Research Laboratory, Ochsner Clinic Foundation, New Orleans, LA, USA

    E. Miller & A. Ponnapakkam

  4. Division of Radioisotope Research, Life Science Research Center, Kagawa University, Kagawa, Japan

    S. Hirofumi

  5. Department of Microbiology, University of Kagawa, Takamatsu, Japan

    S. Miyata

  6. Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    L. J. Suva

  7. Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA

    J. Sakon

  8. Department of Microbiology and Parasitology, Kitasato, University Medical School, Kanagawa, Japan

    O. Matsushita

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  1. Tulasi Ponnapakkam
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  2. R. Katikaneni
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  9. O. Matsushita
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  10. R. C. Gensure
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Correspondence to Tulasi Ponnapakkam.

Additional information

PTH-CBD is patented and exclusively licensed to BiologicsMD (patent number US 2010/0129341 A1). R. C. Gensure is chief medical officer of Biologics MD. J. Sakon and R. C. Gensure own stock in BiologicsMD.

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Ponnapakkam, T., Katikaneni, R., Miller, E. et al. Monthly Administration of a Novel PTH-Collagen Binding Domain Fusion Protein is Anabolic in Mice. Calcif Tissue Int 88, 511–520 (2011). https://doi.org/10.1007/s00223-011-9485-1

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  • DOI: https://doi.org/10.1007/s00223-011-9485-1

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