title: Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity.
abstract: Bone fractures remain a serious health burden and prevention and enhanced healing of fractures have been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1(+/-)) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2(c/c);Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1(+/-) mice were crossed with Bmp2(c/c);Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy.
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, 185 Cambridge Street, Boston, MA 02114, USA. Electronic address: Giuseppe_Intini@hsdm.harvard.edu.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Intini
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D017102:Fracture Healing / Q000502:physiology*; D057895:Haploinsufficiency; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D055114:X-Ray Microtomography
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins
keywords: BMP signaling; Bmp2; Bone homeostasis; Dkk1; Fracture healing; Wnt signaling