Osteopontin deficiency enhances anabolic action of EP4 agonist at a sub-optimal dose in bone.
Osteoporosis is one of the most widespread and destructive bone diseases in our modern world. There is a great need for anabolic agents for bone which could reverse this disease, but few are available for clinical use. Prostaglandin E receptor (EP4) agonist (EP4A) is one of the very few anabolic agents for bone in rat, but its systemic efficacy against bone loss at sub-optimal dose is limited in mice. As osteoblasts are regulated by extracellular matrix proteins, we tested whether deficiency of osteopontin (OPN), a secreted phosphorylated protein, could modulate the effects of EP4A (ONO-AE1-329) treatment at 30 microg/kg body weight, a sub-optimal dose, for 5 days/week for 4 weeks. OPN deficiency enhanced the anabolic effects of EP4A on bone volume. Histomorphometric analysis indicated that EP4A increased mineral apposition rate as well as bone formation rate in OPN-deficient but not in wild-type mice. Neither OPN deficiency nor EP4A altered osteoclast parameters. Importantly, OPN deficiency enhanced the direct anabolic action of EP4A locally injected onto the parietal bone in inducing new bone formation. Combination of OPN deficiency and EP4A treatment caused an increase in mineralized nodule formation in the cultures of bone marrow cells. Finally, OPN deficiency enhanced anabolic action of EP4A in the mice subjected to ovariectomy. These data indicate that OPN deficiency enhances the actions of EP4A at sub-optimal dose.
Kato
Norihiko
N
Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10 Kanda-Surugadai 2-Chome, Tokyo, Japan.
Kitahara
Keiichiro
K
Rittling
Susan R
SR
Nakashima
Kazuhisa
K
Denhardt
David T
DT
Kurosawa
Hisashi
H
Ezura
Yoichi
Y
Noda
Masaki
M
D000469:Alkaline Phosphatase / Q000097:blood / Q000235:genetics; D000596:Amino Acids / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D004334:Drug Administration Schedule; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism*; D015870:Gene Expression; D007279:Injections, Subcutaneous; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D053495:Osteopontin / Q000172:deficiency*; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism; D010052:Ovariectomy; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000076182:Sp7 Transcription Factor; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000235:genetics
C429966:APS-999 Na; D000596:Amino Acids; D015415:Biomarkers; D024042:Collagen Type I; D012333:RNA, Messenger; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D013438:Sulfhydryl Compounds; D013876:Thiophenes; D014157:Transcription Factors; D053495:Osteopontin; C036020:deoxypyridinoline; D000469:Alkaline Phosphatase