The anabolic action of intermittent PTH in combination with cathepsin K inhibitor or alendronate differs depending on the remodeling status in bone in ovariectomized mice.
We hypothesized that the anabolic action of parathyroid hormone (PTH) with the anti-catabolic agents cathepsin K inhibitor and alendronate differs depending on the remodeling status in the bone. C57/BL/6J mice, 8 weeks of age, were subjected to ovariectomized (OVX) or sham surgery. At 6 weeks after surgery, the mice were treated with cathepsin K inhibitor, alendronate, or a vehicle (daily, for 8 weeks), with or without PTH (1-34) (5 times/week, for the last 4 weeks). We assessed the bone chemical markers of the serum and urine, bone mineral density (BMD), histomorphomery in the primary and secondary spongiosa of the proximal tibia after fluorescence labeling, primary cell culture, and mRNA expressions in bone marrow cells. Cathepsin K inhibitor and alendronate significantly increased the BMD and the bone volume of the primary and secondary spongiosa, with a reduction of the urinary C-telopeptide of type I collagen that was increased by OVX, respectively. Cathepsin K inhibitor augmented the anabolic action of PTH on the BMD and bone volume at both the primary and secondary spongiosa, while alendronate had the same effect on the BMD and bone volume only at the primary spongiosa. Cathepsin K inhibitor did not decrease serum osteocalcin with or without PTH, while alendronate did decrease it. Cathepsin K inhibitor did not decrease the values of osteoclast number or bone formation rate with or without PTH, while alendronate decreased those values and increased osteoclast apoptosis. The combination of PTH and cathepsin K inhibitor increased alkaline phosphatase-positive CFU-f formation and c-fos, osterix, and osteocalcin mRNA expressions of bone marrow cells as well as PTH alone, while the combination of PTH and alendronate decreased those values. This study demonstrated that alendronate enhances the anabolic action of PTH at the primary spongiosa, but blunts it in the remodeling trabecular bone, while cathepsin K inhibitor enhances the action at both sites in OVX mice. In conclusion, the anabolic action of intermittent PTH in combination with cathepsin K inhibitor or alendronate differs depending on the remodeling status of bone in OVX mice.
Yamane
Hirotoshi
H
Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. ne-yama@med.uoeh-u.ac.jp
Sakai
Akinori
A
Mori
Toshiharu
T
Tanaka
Shinya
S
Moridera
Kuniaki
K
Nakamura
Toshitaka
T
D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D003401:Creatine / Q000652:urine; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013977:Tibia / Q000166:cytology / Q000187:drug effects
D010281:Parathyroid Hormone; D015675:Osteocalcin; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D003401:Creatine; D019386:Alendronate