title: Stk11 (Lkb1) deletion in the osteoblast lineage leads to high bone turnover, increased trabecular bone density and cortical porosity.
abstract: The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/Lkb1 is a critical serine-threonine protein kinase in the inhibition of mTOR pathway action. In the mammalian skeleton, Stk11 regulates the transition between immature and hypertrophic chondrocytes. Here, we have focused on the action of Stk11in the osteoblast lineage through osteoblast specific-removal of Stk11 activity. In the mouse model system, specification and primary organization of the neonatal boney skeleton is independent of Stk11. However, histological, molecular and micro-CT analysis revealed a marked perturbation of normal bone development evident in the immediate post-natal period. Cortical bone was unusually porous displaying a high rate of turnover with new trabeculae forming in the endosteal space. Trabecular bone also showed enhanced turnover and marked increase in the density of trabeculae and number of osteoclasts. Though mutants showed an expansion of bone volume and trabecular number, their bone matrix comprised large amounts of osteoid and irregularly deposited woven bone highlighted by diffuse fluorochrome labeling. Additionally, we observed an increase in fibroblast-like cells associated with trabecular bone in Stk11 mutants. Stk11 down-regulates mTORC1 activity through control of upstream modulators of the AMP kinase family: an increase in the levels of the phosphorylated ribosomal protein S6, a target of mTORC1-mediated kinase activity, on osteoblast removal of Stk11 suggests deregulated mTORC1 activity contributes to the osteoblast phenotype. These data demonstrate Stk11 activity within osteoblasts is critical for the development of normally structured bone regulating directly the number and coordinated actions of osteoblasts, and indirectly osteoclast number.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine and Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Lick Pui
authors.initials: LP
authors.lastname: Lai
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA; Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.affiliation: Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA; Harvard Medical School, Department of Medicine and Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine and Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA. Electronic address: amcmahon@med.usc.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001846:Bone Development / Q000502:physiology*; D016723:Bone Remodeling / Q000502:physiology*; D019070:Cell Lineage; D005269:Femur / Q000000981:diagnostic imaging; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D016062:Porosity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: Histomorphometry; Osteoblast differentiation; Peritrabecular marrow fibrosis; Serine/threonine kinase 11 (Stk11/Lkb1); Woven bone; mTOR signaling