title: Midkine-deficiency increases the anabolic response of cortical bone to mechanical loading.
abstract: The adaptive response of bone to load is dependent on molecular factors, including growth factor signaling, which is involved in the regulation of proliferation, differentiation and function of osteoblasts and osteoclasts. Based on a recent study, which has shown that the deficiency of growth factor midkine (Mdk) in mice at 12 and 18 months of age resulted in increased trabecular bone formation, we hypothesized that mechanically-induced bone remodeling may, at least in part, be dependent on Mdk expression. To investigate this, we loaded the ulnae of Mdk-deficient mice and appropriate wild-type mice at the age of 12 months using the in vivo ulna loading model. Histomorphometric quantification of the periosteal bone demonstrated an increased mineralizing surface, mineral apposition rate, and bone formation rate in ulnae of Mdk-deficient mice compared to wild-type mice in response to loading. Because Mdk has been shown to bind to a complex of receptor-type protein tyrosine phosphatase zeta (Ptprz) and low density lipoprotein receptor-related protein-6 (Lrp-6) together with the α4β1- and α6β1-integrins, we performed in vitro studies using osteoblastic cells, transiently over-expressing Mdk, Wnt-3a, and Ptprz to evaluate whether Mdk has a role in regulating bone formation by modulating Wnt signaling. We observed a negative effect of Mdk on Wnt signaling, the extent of which appeared to be dependent on Ptprz expression. Moreover, we performed in vitro loading studies with osteoblasts treated with recombinant Mdk and observed a negative effect on the expression of Wnt target genes, which play a critical role in osteoblast proliferation. In summary, our data demonstrate that Mdk-deficiency in mice has an anabolic effect on mechanically induced cortical bone formation. This could be due to an improved osteoblast function based on an enhancement of β-catenin-dependent Wnt signaling by both Mdk-deficiency and mechanical loading.
authors.affiliation: Institute of Orthopedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany. astrid.liedert@uni-ulm.de
authors.forename: Astrid
authors.initials: A
authors.lastname: Liedert
authors.forename: Laura
authors.initials: L
authors.lastname: Mattausch
authors.forename: Viktoria
authors.initials: V
authors.lastname: Röntgen
authors.forename: Robert
authors.initials: R
authors.lastname: Blakytny
authors.forename: Daniel
authors.initials: D
authors.lastname: Vogele
authors.forename: Marcus
authors.initials: M
authors.lastname: Pahl
authors.forename: Ronny
authors.initials: R
authors.lastname: Bindl
authors.forename: Claudia
authors.initials: C
authors.lastname: Neunaber
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Sheila
authors.initials: S
authors.lastname: Harroch
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001842:Bone and Bones / Q000503:physiopathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D017931:DNA Primers; D051379:Mice; D008810:Mice, Inbred C57BL; D000078792:Midkine; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D016207:Cytokines; D017931:DNA Primers; D000078792:Midkine