Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice.
Intermittent parathyroid hormone (PTH) treatment is a potent bone anabolic principle that suppresses expression of the bone formation inhibitor Sost. We addressed the relevance of Sost suppression for PTH-induced bone anabolism in vivo using mice with altered Sost gene dosage. Six-month-old Sost overexpressing and 2-month-old Sost deficient male mice and their wild-type littermates were subjected to daily injections of 100 microg/kg PTH(1-34) or vehicle for a 2-month period. A follow-up study was performed in Sost deficient mice using 40 and 80 microg/kg PTH(1-34). Animals were sacrificed 4 hours after the final PTH administration and Sost expression in long bone diaphyses was determined by qPCR. Bone changes were analyzed in vivo in the distal femur metaphysis by pQCT and ex vivo in the tibia and lumbar spine by DXA. Detailed ex vivo analyses of the femur were performed by pQCT, microCT, and histomorphometry. Overexpression of Sost resulted in osteopenia and Sost deletion in high bone mass. As shown before, PTH suppressed Sost in wild-type mice. PTH treatment induced substantial increases in bone mineral density, content, and cortical thickness and in aging wild-type mice also led to cancellous bone gain owing to amplified bone formation rates. PTH-induced bone gain was blunted at all doses and skeletal sites in Sost overexpressing and deficient mice owing to attenuated bone formation rates, whereas bone resorption was not different from that in PTH-treated wild-type controls. These data suggest that suppression of the bone formation inhibitor Sost by intermittent PTH treatment contributes to PTH bone anabolism.
Kramer
Ina
I
Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Loots
Gabriela G
GG
Studer
Anne
A
Keller
Hansjoerg
H
Kneissel
Michaela
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D005819:Genetic Markers / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D010281:Parathyroid Hormone; C422903:SOST protein, human