Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing.
Recent studies have demonstrated that intermittent administration of parathyroid hormone (PTH) enhances osteogenesis (hard callus formation) and increases mechanical strength in experimental fracture healing. Thus far, however, effects of PTH on chondrogenesis (soft callus formation) during fracture healing have not been fully elucidated. In the present study, we analyzed the underlying molecular mechanism by which exogenous PTH would affect chondrogenesis in a model of experimental fracture healing. Unilateral femoral fractures were produced in 2-month-old Sprague-Dawley rats. Daily subcutaneous injections of 10 microg/kg of recombinant human PTH(1-34) [rhPTH(1-34)] were administered over a 28-day period of fracture healing. Control animals were injected with vehicle solution (normal saline) alone. The results showed that, on day 14 after fracture, cartilage area in the PTH-treated group was significantly increased (1.4-fold) compared with the controls, but this increase was not observed at days 21 and 28. In the early stage of chondrogenesis (days 4-7), cell proliferation, expressed as the rate of proliferating cell nuclear antigen-positive cells, was increased in mesenchymal (chondroprogenitor) cells but not chondrocytes in the PTH-treated group compared with controls. In addition, gene expression of SOX-9 was up-regulated in the PTH-treated group on day 4 (1.4-fold), and this was accompanied by enhanced expression of pro-alpha1 (II) collagen (1.8-fold). After 14 days, there were no significant differences between groups in either cell proliferation or the expression levels of cartilage differentiation-related genes (SOX-9, pro-alpha1 (II) collagen, pro-alpha1 (X) collagen and osteopontin). These results suggest that intermittent treatment with low-dose rhPTH(1-34) induces a larger cartilaginous callus but does not delay chondrocyte differentiation during fracture healing.
Nakazawa
Tetsuro
T
Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8677, Japan.
Nakajima
Arata
A
Shiomi
Koji
K
Moriya
Hideshige
H
Einhorn
Thomas A
TA
Yamazaki
Masashi
M
D000818:Animals; D002146:Bony Callus / Q000166:cytology / Q000502:physiology; D002356:Cartilage / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects*; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D024043:Collagen Type II / Q000096:biosynthesis / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D006132:Growth Plate / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D055758:SOX9 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology
C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D006609:High Mobility Group Proteins; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D014157:Transcription Factors; C426047:pro-alpha1(V-XI) collagen; D007334:Insulin-Like Growth Factor I; D003094:Collagen