title: BMP receptor signaling is required for postnatal maintenance of articular cartilage.
abstract: Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.
authors.affiliation: Department of Developmental Biology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Rountree
authors.forename: Michael
authors.initials: M
authors.lastname: Schoor
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Marks
authors.forename: Vincent
authors.initials: V
authors.lastname: Harley
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: David M
authors.initials: DM
authors.lastname: Kingsley
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism*; D049109:Cell Proliferation; D022202:Chromosomes, Artificial, Bacterial / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D055428:Growth Differentiation Factor 5; D007249:Inflammation; D019426:Integrases / Q000378:metabolism; D007596:Joints / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010003:Osteoarthritis / Q000378:metabolism; D010641:Phenotype; D011995:Recombination, Genetic; D012307:Risk Factors; D015398:Signal Transduction; D013583:Synovial Membrane / Q000196:embryology*; D013997:Time Factors
chemical_list: D019485:Bone Morphogenetic Proteins; C525893:GDF5 protein, human; C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; C045073:Cre recombinase; D019426:Integrases