Increased trabecular bone formation in mice lacking the growth factor midkine.
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Increased trabecular bone formation in mice lacking the growth factor midkine. / Neunaber, Claudia; Catalá-Lehnen, Philip; Beil, Frank Timo; Marshall, Robert-Percy; Kanbach, Vincent; Baranowsky, Anke; Lehmann, Wolfgang; Streichert, Thomas; Ignatius, Anita; Muramatsu, Takashi; Schinke, Thorsten; Amling, Michael.
In: J BONE MINER RES, Vol. 25, No. 8, 8, 2010, p. 1724-1735.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Increased trabecular bone formation in mice lacking the growth factor midkine.
AU - Neunaber, Claudia
AU - Catalá-Lehnen, Philip
AU - Beil, Frank Timo
AU - Marshall, Robert-Percy
AU - Kanbach, Vincent
AU - Baranowsky, Anke
AU - Lehmann, Wolfgang
AU - Streichert, Thomas
AU - Ignatius, Anita
AU - Muramatsu, Takashi
AU - Schinke, Thorsten
AU - Amling, Michael
PY - 2010
Y1 - 2010
N2 - Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptn-deficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome-wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy.
AB - Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptn-deficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome-wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy.
KW - Animals
KW - Female
KW - Gene Expression Regulation
KW - Genotype
KW - Mice
KW - Osteogenesis physiology
KW - Phenotype
KW - Analysis of Variance
KW - Aging metabolism
KW - Bone Resorption metabolism
KW - Bone and Bones metabolism
KW - Cytokines deficiency
KW - Organ Size
KW - Osteoblasts metabolism
KW - Ovariectomy
KW - Animals
KW - Female
KW - Gene Expression Regulation
KW - Genotype
KW - Mice
KW - Osteogenesis physiology
KW - Phenotype
KW - Analysis of Variance
KW - Aging metabolism
KW - Bone Resorption metabolism
KW - Bone and Bones metabolism
KW - Cytokines deficiency
KW - Organ Size
KW - Osteoblasts metabolism
KW - Ovariectomy
M3 - SCORING: Zeitschriftenaufsatz
VL - 25
SP - 1724
EP - 1735
JO - J BONE MINER RES
JF - J BONE MINER RES
SN - 0884-0431
IS - 8
M1 - 8
ER -
