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LRP6 in mesenchymal stem cells is required for bone formation during bone growth and bone remodeling 被引量:7

LRP6 in mesenchymal stem cells is required for bone formation during bone growth and bone remodeling
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摘要 Lipoprotein receptor-related protein 6 (LRP6) plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells (MSCs), skeletal stem cells that give rise to osteoblastic lineage, is unknown. In this study, we generated mice lacking LRP6 expression specifically in nestin+ MSCs by crossing nestin-Cre mice with LRP6 flox mice and investigated the functional changes of bone marrow MSCs and skeletal alterations. Mice with LRP6 deletion in nestin+ cells demonstrated reductions in body weight and body length at I and 3 months of age. Bone architecture measured by microCT (uCT) showed a significant reduction in bone mass in both trabecular and cortical bone of homozygous and heterozygous LRP6 mutant mice. A dramatic reduction in the numbers of osteoblasts but much less significant reduction in the numbers of osteoclasts was observed in the mutant mice. Osterix+ osteoprogenitors and osteocalcin+ osteoblasts significantly reduced at the secondary spongiosa area, but only moderately decreased at the primary spongiosa area in mutant mice. Bone marrow MSCs from the mutant mice showed decreased colony forming, cell viability and cell proliferation. Thus, LRP6 in bone marrow MSCs is essential for their survival and proliferation, and therefore, is a key positive regulator for bone formation during skeletal growth and remodeling. Lipoprotein receptor-related protein 6 (LRP6) plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells (MSCs), skeletal stem cells that give rise to osteoblastic lineage, is unknown. In this study, we generated mice lacking LRP6 expression specifically in nestin+ MSCs by crossing nestin-Cre mice with LRP6 flox mice and investigated the functional changes of bone marrow MSCs and skeletal alterations. Mice with LRP6 deletion in nestin+ cells demonstrated reductions in body weight and body length at I and 3 months of age. Bone architecture measured by microCT (uCT) showed a significant reduction in bone mass in both trabecular and cortical bone of homozygous and heterozygous LRP6 mutant mice. A dramatic reduction in the numbers of osteoblasts but much less significant reduction in the numbers of osteoclasts was observed in the mutant mice. Osterix+ osteoprogenitors and osteocalcin+ osteoblasts significantly reduced at the secondary spongiosa area, but only moderately decreased at the primary spongiosa area in mutant mice. Bone marrow MSCs from the mutant mice showed decreased colony forming, cell viability and cell proliferation. Thus, LRP6 in bone marrow MSCs is essential for their survival and proliferation, and therefore, is a key positive regulator for bone formation during skeletal growth and remodeling.
出处 《Bone Research》 SCIE CAS 2014年第1期43-54,共12页 骨研究(英文版)
基金 supported by National Institutes of Health Grant DK083350 to M. W
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  • 1Rajvir Singh,Emily Smith,Mohsen Fathzadeh,Wenzhong Liu,Gwang‐Woong Go,Lakshman Subrahmanyan,Saeed Faramarzi,William McKenna,Arya Mani.Rare Nonconservative LRP6 Mutations Are Associated with Metabolic Syndrome[J].Human Mutation.2013(9)
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