title: Increased trabecular bone formation in mice lacking the growth factor midkine.
abstract: 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.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Neunaber
authors.forename: Philip
authors.initials: P
authors.lastname: Catala-Lehnen
authors.forename: F Timo
authors.initials: FT
authors.lastname: Beil
authors.forename: Robert P
authors.initials: RP
authors.lastname: Marshall
authors.forename: Vincent
authors.initials: V
authors.lastname: Kanbach
authors.forename: Anke
authors.initials: A
authors.lastname: Baranowsky
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lehmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
authors.forename: Takashi
authors.initials: T
authors.lastname: Muramatsu
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
mesh_terms: D000375:Aging / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D000078792:Midkine; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000502:physiology*; D010052:Ovariectomy; D010641:Phenotype
chemical_list: D016207:Cytokines; D000078792:Midkine