title: Role of WNT16 in the regulation of periosteal bone formation in female mice.
abstract: In this study, we evaluated the role of WNT16 in regulating bone size, an important determinant of bone strength. Mice with targeted disruption of the Wnt16 gene exhibited a 24% reduction in tibia cross-sectional area at 12 weeks of age compared with that of littermate wild-type (WT) mice. Histomorphometric studies revealed that the periosteal bone formation rate and mineral apposition rate were reduced (P < .05) by 55% and 32%, respectively, in Wnt16 knockout (KO) vs WT mice at 12 weeks of age. In contrast, the periosteal tartrate resistant acid phosphatase-labeled surface was increased by 20% in the KO mice. Because mechanical strain is an important physiological regulator of periosteal bone formation (BF), we determined whether mechanical loading-induced periosteal BF is compromised in Wnt16 KO mice. Application of 4800-μe strain to the right tibia using a 4-point bending loading method for 2 weeks (2-Hz frequency, 36 cycles per day, 6 days/wk) produced a significant increase in cross-sectional area (11% above that of the unloaded left tibia, P < .05, n = 6) in the WT but not in the KO mice (-0.2% change). Histomorphometric analyses revealed increases in the periosteal bone formation rate and mineral apposition rate in the loaded bones of WT but not KO mice. Wnt16 KO mice showed significant (20%-70%) reductions in the expression levels of markers of canonical (β-catenin and Axin2) but not noncanonical (Nfatc1 and Tnnt2) WNT signaling in the periosteum at 5 weeks of age. Our findings suggest that WNT16 acting via canonical WNT signaling regulates mechanical strain-induced periosteal BF and bone size.
authors.affiliation: Musculoskeletal Disease Center (J.E.W., C.K., S.D., S.M.), VA Loma Linda Healthcare System, Loma Linda, California 92354; Departments of Medicine (J.E.W., C.K., S.M.), Biochemistry (J.E.W., S.M.), and Physiology (S.M.), Loma Linda University, Loma Linda, California 92357; and Metabolism (R.B.), Lexicon Pharmaceuticals, The Woodlands, Texas 77381.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kesavan
authors.forename: Robert
authors.initials: R
authors.lastname: Brommage
authors.forename: Subhashri
authors.initials: S
authors.lastname: Das
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology; D001846:Bone Development / Q000502:physiology*; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010521:Periosteum / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; D051153:Wnt Proteins; C585687:Wnt16 protein, mouse; D012313:RNA