title: Postnatal β-catenin deletion from Dmp1-expressing osteocytes/osteoblasts reduces structural adaptation to loading, but not periosteal load-induced bone formation.
abstract: Mechanical signal transduction in bone tissue begins with load-induced activation of several cellular pathways in the osteocyte population. A key pathway that participates in mechanotransduction is Wnt/Lrp5 signaling. A putative downstream mediator of activated Lrp5 is the nucleocytoplasmic shuttling protein β-catenin (βcat), which migrates to the nucleus where it functions as a transcriptional co-activator. We investigated whether osteocytic βcat participates in Wnt/Lrp5-mediated mechanotransduction by conducting ulnar loading experiments in mice with or without chemically induced βcat deletion in osteocytes. Mice harboring βcat floxed loss-of-function alleles (βcat(f/f)) were bred to the inducible osteocyte Cre transgenic (10)(kb)Dmp1-CreERt2. Adult male mice were induced to recombine the βcat alleles using tamoxifen, and intermittent ulnar loading sessions were applied over the following week. Although adult-onset deletion of βcat from Dmp1-expressing cells reduced skeletal mass, the bone tissue was responsive to mechanical stimulation as indicated by increased relative periosteal bone formation rates in recombined mice. However, load-induced improvements in cross sectional geometric properties were compromised in recombined mice. The collective results indicate that the osteoanabolic response to loading can occur on the periosteal surface when β-cat levels are significantly reduced in Dmp1-expressing cells, suggesting that either (i) only low levels of β-cat are required for mechanically induced bone formation on the periosteal surface, or (ii) other additional downstream mediators of Lrp5 might participate in transducing load-induced Wnt signaling.
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Kang
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Hong
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA. Electronic address: arobling@iupui.edu.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
mesh_terms: D015502:Absorptiometry, Photon; D000222:Adaptation, Physiological; D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density; D000071538:Cortical Bone / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D017353:Gene Deletion; D051379:Mice; D009132:Muscles / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism*; D010011:Osteocytes / Q000378:metabolism*; D010012:Osteogenesis; D010521:Periosteum / Q000473:pathology / Q000503:physiopathology*; D019076:Transgenes; D016474:Weight-Bearing; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D051176:beta Catenin
keywords: Loading; Mechanical strain; Osteoporosis; Wnt; β-Catenin