title: Sprouty2 regulates endochondral bone formation by modulation of RTK and BMP signaling.
abstract: Skeletal development is regulated by the coordinated activity of signaling molecules that are both produced locally by cartilage and bone cells and also circulate systemically. During embryonic development and postnatal bone remodeling, receptor tyrosine kinase (RTK) superfamily members play critical roles in the proliferation, survival, and differentiation of chondrocytes, osteoblasts, osteoclasts, and other bone cells. Recently, several molecules that regulate RTK signaling have been identified, including the four members of the Sprouty (Spry) family (Spry1-4). We report that Spry2 plays an important role in regulation of endochondral bone formation. Mice in which the Spry2 gene has been deleted have defective chondrogenesis and endochondral bone formation, with a postnatal decrease in skeletal size and trabecular bone mass. In these constitutive Spry2 mutants, both chondrocytes and osteoblasts undergo increased cell proliferation and impaired terminal differentiation. Tissue-specific Spry2 deletion by either osteoblast- (Col1-Cre) or chondrocyte- (Col2-Cre) specific drivers led to decreased relative bone mass, demonstrating the critical role of Spry2 in both cell types. Molecular analyses of signaling pathways in Spry2(-/-) mice revealed an unexpected upregulation of BMP signaling and decrease in RTK signaling. These results identify Spry2 as a critical regulator of endochondral bone formation that modulates signaling in both osteoblast and chondrocyte lineages.
authors.affiliation: Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, United States; Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Adriane
authors.initials: A
authors.lastname: Joo
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Roger
authors.initials: R
authors.lastname: Long
authors.affiliation: Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, United States; Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Alexander
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, United States; Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, United States; Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, United States. Electronic address: ophir.klein@ucsf.edu.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism; D000071556:Cancellous Bone / Q000473:pathology; D002356:Cartilage / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism; D020219:Chondrogenesis; D004622:Embryo, Mammalian / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D017346:Protein Serine-Threonine Kinases; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse
keywords: BMPs; Chondrocytes; Endochondral bone formation; FGFs; Sprouty