Monthly administration of a novel PTH-collagen binding domain fusion protein is anabolic in mice

Tulasi Ponnapakkam, R. Katikaneni, E. Miller, A. Ponnapakkam, S. Hirofumi, S. Miyata, L. J. Suva, J. Sakon, O. Matsushita, R. C. Gensure

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)511-520
Number of pages10
JournalCalcified Tissue International
Volume88
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Parathyroid Hormone
Collagen
Bone and Bones
Bone Density
Protein Domains
Parathyroid Hormone Receptor Type 1
Parathyroid Hormone-Related Protein
Anabolic Agents
Postmenopausal Osteoporosis
Collagen Type I
Serum
Inbred C57BL Mouse
Alkaline Phosphatase
Proteins
Calcium
Skin
Peptides

Keywords

  • Bone mineral density
  • Collagen binding domain
  • Collagenase
  • Mice
  • Osteoporosis
  • Parathyroid hormone

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Ponnapakkam, T., Katikaneni, R., Miller, E., Ponnapakkam, A., Hirofumi, S., Miyata, S., ... Gensure, R. C. (2011). Monthly administration of a novel PTH-collagen binding domain fusion protein is anabolic in mice. Calcified Tissue International, 88(6), 511-520. https://doi.org/10.1007/s00223-011-9485-1

Monthly administration of a novel PTH-collagen binding domain fusion protein is anabolic in mice. / Ponnapakkam, Tulasi; Katikaneni, R.; Miller, E.; Ponnapakkam, A.; Hirofumi, S.; Miyata, S.; Suva, L. J.; Sakon, J.; Matsushita, O.; Gensure, R. C.

In: Calcified Tissue International, Vol. 88, No. 6, 06.2011, p. 511-520.

Research output: Contribution to journalArticle

Ponnapakkam, T, Katikaneni, R, Miller, E, Ponnapakkam, A, Hirofumi, S, Miyata, S, Suva, LJ, Sakon, J, Matsushita, O & Gensure, RC 2011, 'Monthly administration of a novel PTH-collagen binding domain fusion protein is anabolic in mice', Calcified Tissue International, vol. 88, no. 6, pp. 511-520. https://doi.org/10.1007/s00223-011-9485-1
Ponnapakkam, Tulasi ; Katikaneni, R. ; Miller, E. ; Ponnapakkam, A. ; Hirofumi, S. ; Miyata, S. ; Suva, L. J. ; Sakon, J. ; Matsushita, O. ; Gensure, R. C. / Monthly administration of a novel PTH-collagen binding domain fusion protein is anabolic in mice. In: Calcified Tissue International. 2011 ; Vol. 88, No. 6. pp. 511-520.
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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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AU - Ponnapakkam, Tulasi

AU - Katikaneni, R.

AU - Miller, E.

AU - Ponnapakkam, A.

AU - Hirofumi, S.

AU - Miyata, S.

AU - Suva, L. J.

AU - Sakon, J.

AU - Matsushita, O.

AU - Gensure, R. C.

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AB - 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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KW - Osteoporosis

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