Early response of bone marrow osteoprogenitors to skeletal unloading and sclerostin antibody.
Sclerostin functions as an antagonist to Wnt signaling and inhibits bone-forming activity. We studied the effects of skeletal unloading and treatment with sclerostin antibody (Scl-Ab) on mesenchymal stem cell, osteoprogenitor and osteoclast precursor pools, and their relationship to bone formation and resorption. Male C57BL/6 mice (5-months-old) were hind limb unloaded for 1 week or allowed normal ambulation and treated with Scl-Ab (25 mg/kg, s.c. injections on days 1 and 4) or placebo. Unloading decreased the serum concentration of bone formation marker P1NP (-35 %), number of colony-forming units (CFU) (-38 %), alkaline phosphatase-positive CFUs (CFU-AP+) (-51 %), and calcified nodules (-35 %); and resulted in a fourfold increase in the number of osteoclast precursors. The effects of Scl-Ab treatment on unloaded and normally loaded mice were nearly identical; Scl-Ab increased serum P1NP and the number of CFU, CFU-AP+, and calcified nodules in ex vivo cultures; and increased osteoblast and bone mineralizing surfaces in vivo. Although the marrow-derived osteoclast precursor population increased with Scl-Ab, the bone osteoclast surface did not change, and the serum concentration of osteoclast activity marker TRACP5b decreased. Our data suggest that short-term Scl-Ab treatment can prevent the decrease in osteoprogenitor population associated with skeletal unloading and increase osteoblast surface and bone mineralizing surface in unloaded animals. The anabolic effects of Scl-Ab treatment on bone are preserved during skeletal unloading. These findings suggest that Scl-Ab treatment can both increase bone formation and decrease bone resorption, and provide a new means for prevention and treatment of disuse osteoporosis.
Division of Endocrinology, Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA.
Mohammad
M
Shahnazari
Thomas
T
Wronski
Vivian
V
Chu
Alyssa
A
Williams
Alicia
A
Leeper
Marina
M
Stolina
Hua Zhu
HZ
Ke
Bernard
B
Halloran
D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism*; D001862:Bone Resorption; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019417:Hindlimb Suspension; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; C486030:Sost protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase