Over-expression of TIMP-1 in osteoblasts increases the anabolic response to PTH.
Intermittent PTH treatment induces structural changes that affect cancellous bone mass and have led to its indication for the treatment of osteoporosis. PTH is also known to upregulate the expression of matrix metalloproteinases (MMP) in osteoblasts. We wanted to find out whether inhibiting osteoblastic MMPs can affect the anabolic action of PTH in vivo. We had shown previously that mice over-expressing TIMP-1 (tissue inhibitor of MMPs) specifically in osteoblasts display an increase in bone mineral density and bone mass combined with an overall decrease in bone turnover. In the present study, 10-week-old wild-type (WT) and transgenic (TG) mice were treated with PTH at 40 microg/kg/day for 1.5 months. DEXA analysis was performed before and after treatment, and histomorphometric and molecular analysis were carried out at the end of the experiment. Our findings indicate that the transgene boosted the anabolic action of PTH. The femurs of PTH-treated TG mice displayed a greater increase in bone mineral density and trabecular bone volume than treated WT mice. Interestingly, the positive effect of the transgene on the action of PTH resulted from both reduced bone resorption activity and an increase in the bone formation rate. Osteoclastic surfaces that were increased in PTH-treated WT mice remained unchanged in TG mice, suggesting a decrease in osteoclastic differentiation. Histomorphometric data also indicate that PTH administration increased osteoblast activity in TG mice and affected the number of osteoblasts in WT mice. In conclusion, we demonstrate that inhibiting osteoblastic MMPs can potentiate the anabolic effect of PTH by decreasing osteoclast activity and increasing osteoblast activity. Our data also suggest that osteoblastic MMPs have some role in mediating the anabolic effects of PTH in vivo and indicate that inhibitors of MMPs could constitute a new therapy for degenerative diseases.
Merciris
D
D
INSERM U606, Hôpital Lariboisière, Centre Viggo Petersen, 2 rue Ambroise Paré 75475 Paris Cedex 10, France.
Schiltz
C
C
Legoupil
N
N
Marty-Morieux
C
C
de Vernejoul
M C
MC
Geoffroy
V
V
D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001862:Bone Resorption / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005269:Femur / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011859:Radiography; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D010281:Parathyroid Hormone; D019715:Tissue Inhibitor of Metalloproteinase-1; D008666:Metalloendopeptidases