Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice

Sarah K. Gray, Meghan Elizabeth McGee Lawrence, Jennifer L. Sanders, Keith W. Condon, Chung Jui Tsai, Seth W. Donahue

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28. nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6. weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic treatment for DMD-induced osteoporosis.

Original languageEnglish (US)
Pages (from-to)578-585
Number of pages8
JournalBone
Volume51
Issue number3
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

Fingerprint

Ursidae
Anabolic Agents
Dystrophin
Parathyroid Hormone
Inbred mdx Mouse
Duchenne Muscular Dystrophy
Bone and Bones
Osteoporosis
Femur
Osteoblasts
Tibia
Therapeutics
Cancellous Bone
Hibernation
Muscles
Neuromuscular Diseases
Premature Mortality
Calcium Signaling
Osteoclasts
Subcutaneous Injections

Keywords

  • Black bear
  • DMD model
  • Mdx
  • Osteoporosis
  • PTH

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice. / Gray, Sarah K.; McGee Lawrence, Meghan Elizabeth; Sanders, Jennifer L.; Condon, Keith W.; Tsai, Chung Jui; Donahue, Seth W.

In: Bone, Vol. 51, No. 3, 01.09.2012, p. 578-585.

Research output: Contribution to journalArticle

Gray, Sarah K. ; McGee Lawrence, Meghan Elizabeth ; Sanders, Jennifer L. ; Condon, Keith W. ; Tsai, Chung Jui ; Donahue, Seth W. / Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice. In: Bone. 2012 ; Vol. 51, No. 3. pp. 578-585.
@article{e8fc3579995d4e52b3c49a292a90e5a6,
title = "Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice",
abstract = "Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28. nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6. weeks. Vehicle-treated mdx mice had 44{\%} lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic treatment for DMD-induced osteoporosis.",
keywords = "Black bear, DMD model, Mdx, Osteoporosis, PTH",
author = "Gray, {Sarah K.} and {McGee Lawrence}, {Meghan Elizabeth} and Sanders, {Jennifer L.} and Condon, {Keith W.} and Tsai, {Chung Jui} and Donahue, {Seth W.}",
year = "2012",
month = "9",
day = "1",
doi = "10.1016/j.bone.2012.05.003",
language = "English (US)",
volume = "51",
pages = "578--585",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice

AU - Gray, Sarah K.

AU - McGee Lawrence, Meghan Elizabeth

AU - Sanders, Jennifer L.

AU - Condon, Keith W.

AU - Tsai, Chung Jui

AU - Donahue, Seth W.

PY - 2012/9/1

Y1 - 2012/9/1

N2 - Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28. nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6. weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic treatment for DMD-induced osteoporosis.

AB - Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28. nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6. weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic treatment for DMD-induced osteoporosis.

KW - Black bear

KW - DMD model

KW - Mdx

KW - Osteoporosis

KW - PTH

UR - http://www.scopus.com/inward/record.url?scp=84864776270&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864776270&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2012.05.003

DO - 10.1016/j.bone.2012.05.003

M3 - Article

C2 - 22584007

AN - SCOPUS:84864776270

VL - 51

SP - 578

EP - 585

JO - Bone

JF - Bone

SN - 8756-3282

IS - 3

ER -