Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1-34).
Recent reports have demonstrated that intermittent treatment with parathyroid hormone (1-34) [PTH(1-34)] increases callus formation and mechanical strength in experimental fracture healing. However, little is known about the optimal dose required for enhancement of fracture repair or the molecular mechanisms by which PTH regulates the healing process. In this study, we analyzed the underlying molecular mechanisms by which PTH affects fracture healing and tested the hypothesis that intermittent low-dose treatment with human PTH(1-34) can increase callus formation and mechanical strength. Unilateral femoral fractures were produced and a daily subcutaneous injection of 10 microg/kg of PTH(1-34) was administered during the entire healing period. Control animals were injected with vehicle solution alone. The results showed that on day 28 and day 42 after fracture, bone mineral content (BMC), bone mineral density (BMD), and ultimate load to failure of the calluses were significantly increased in the PTH-treated group compared with controls (day 28, 61, 46, and 32%; day 42, 119, 74, and 55%, respectively). The number of proliferating cell nuclear antigen (PCNA)-positive subperiosteal osteoprogenitor cells was significantly increased in the calluses of the PTH-treated group on day 2, and TRAP+ multinucleated cells were significantly increased in areas of callus cancellous bone on day 7. The levels of expression of type I collagen (COLlA1), osteonectin (ON), ALP, and osteocalcin (OC) mRNA were increased markedly in the PTH-treated group and accompanied by enhanced expression of insulin-like growth factor (IGF)-I mRNA during the early stages of healing (days 4-7). The increased expression of COL1A1, ON, ALP, and OC mRNA continued during the later stages of healing (days 14-21) despite a lack of up-regulation of IGF-I mRNA. These results suggest that treatment of fractures with intermittent low dose PTH(1-34) enhances callus formation by the early stimulation of proliferation and differentiation of osteoprogenitor cells, increases production of bone matrix proteins, and enhances osteoclastogenesis during the phase of callus remodeling. The resultant effect to increase callus mechanical strength supports the concept that clinical investigations on the ability of injectable low-dose PTH(1-34) to enhance fracture healing are indicated.
Nakajima
Arata
A
Department of Orthopedic Surgery, Chiba University Graduate School of Medicine, Japan.
Shimoji
Naoshi
N
Shiomi
Koji
K
Shimizu
Sumito
S
Moriya
Hideshige
H
Einhorn
Thomas A
TA
Yamazaki
Masashi
M
D015502:Absorptiometry, Photon; D000469:Alkaline Phosphatase / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D002146:Bony Callus / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects; D003094:Collagen / Q000187:drug effects / Q000235:genetics; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017102:Fracture Healing / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000235:genetics; D008297:Male; D015675:Osteocalcin / Q000187:drug effects / Q000235:genetics; D015676:Osteonectin / Q000187:drug effects / Q000235:genetics; D010281:Parathyroid Hormone / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D015676:Osteonectin; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D000469:Alkaline Phosphatase