title: Adverse Effects of Osteocytic Constitutive Activation of ß-Catenin on Bone Strength and Bone Growth.
abstract: The activation of the canonical Wnt/β-catenin signaling pathway in both mesenchymal stem cells and osteoblasts has been demonstrated to increase bone mass, showing promise for the treatment of low bone volume conditions such as osteoporosis. However, the possible side effects of manipulating this pathway have not been fully addressed. Previously, we reported that the constitutive activation of ß-catenin in osteoblasts impaired vertebral linear growth. In the present study, β-catenin was constitutively activated in osteocytes by crossing Catnb+/lox(exon 3) mice with dentin matrix protein 1(DMP1)-Cre transgenic mice, and the effects of this activation on bone mass, bone growth and bone strength were then observed. DMP1-Cre was found to be predominantly expressed in osteocytes, with weak expression in a small portion of osteoblasts and growth plate chondrocytes. After the activation, the cancellous bone mass was dramatically increased, almost filling the entire bone marrow cavity in long bones. However, bone strength decreased significantly. Thinner and more porous cortical bone along with impaired mineralization were responsible for the decrease in bone strength. Furthermore, the mice showed shorter stature with impaired linear growth of the long bones. Moreover, the concentration of serum phosphate decreased significantly after the activation of ß-catenin, and a high inorganic phosphate (Pi) diet could partially rescue the phenotype of decreased mineralization level and impaired linear growth. Taken together, the constitutive activation of β-catenin in osteocytes may increase cancellous bone mass; however, the activation also had adverse effects on bone strength and bone growth. These adverse effects should be addressed before the adoption of any therapeutic clinical application involving adjustment of the Wnt/β-catenin signaling pathway.
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.|Department of Orthopedics, the 118th Hospital of the Chinese People's Liberation Army, Wenzhou, China.
authors: Sixu
authors: S
authors: Chen
authors: Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, USA.
authors: Jianquan
authors: J
authors: Feng
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.
authors: Quanwei
authors: Q
authors: Bao
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.
authors: Ang
authors: A
authors: Li
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.
authors: Bo
authors: B
authors: Zhang
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.
authors: Yue
authors: Y
authors: Shen
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.
authors: Yufeng
authors: Y
authors: Zhao
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.
authors: Qingshan
authors: Q
authors: Guo
authors: Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, USA.
authors: Junjun
authors: J
authors: Jing
authors: Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, USA.
authors: Shuxian
authors: S
authors: Lin
authors: State Key Laboratory of Trauma, Burn, and Combined Injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing, China.
authors: Zhaowen
authors: Z
authors: Zong
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001846:Bone Development; D001842:Bone and Bones / Q000378:metabolism* / Q000502:physiology*; D002113:Calcification, Physiologic; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008822:Mice, Transgenic; D010011:Osteocytes / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D051176:beta Catenin; C045073:Cre recombinase; D019426:Integrases
keywords: BONE REMODELING; GENETIC ANIMAL MODELS; MATRIX MINERALIZATION; OSTEOCYTES; β-CATENIN