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 28nmol/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.
authors.affiliation: Michigan Tech University, Dept. of Biomedical Engineering, 309 M&M Bldg., 1400 Townsend Dr., Houghton, MI 49931, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Gray
authors.forename: Meghan E
authors.initials: ME
authors.lastname: McGee-Lawrence
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sanders
authors.forename: Keith W
authors.initials: KW
authors.lastname: Condon
authors.forename: Chung-Jui
authors.initials: CJ
authors.lastname: Tsai
authors.forename: Seth W
authors.initials: SW
authors.lastname: Donahue
mesh_terms: D000595:Amino Acid Sequence; D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D000880:Anthraquinones / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001696:Biomechanical Phenomena / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D016189:Dystrophin / Q000172:deficiency* / Q000378:metabolism; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009929:Organ Size / Q000187:drug effects; D010281:Parathyroid Hormone / Q000737:chemistry / Q000494:pharmacology*; D013194:Staining and Labeling; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects; D001503:Ursidae / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D045930:Anabolic Agents; D000880:Anthraquinones; D016189:Dystrophin; D010281:Parathyroid Hormone; C010078:alizarin; D000242:Cyclic AMP