During the assembly of the musculoskeletal system, bone ridges provide a stable anchoring point and stress dissipation for the attachment of muscles via tendons to the skeleton. In this study, we investigate the development of the deltoid tuberosity as a model for bone ridge formation. We show that the deltoid tuberosity develops through endochondral ossification in a two-phase process: initiation is regulated by a signal from the tendons, whereas the subsequent growth phase is muscle dependent. We then show that the transcription factor scleraxis (SCX) regulates Bmp4 in tendon cells at their insertion site. The inhibition of deltoid tuberosity formation and several other bone ridges in embryos in which Bmp4 expression was blocked specifically in Scx-expressing cells implicates BMP4 as a key mediator of tendon effects on bone ridge formation. This study establishes a mechanistic basis for tendon-skeleton regulatory interactions during musculoskeletal assembly and bone secondary patterning.
Bibliographical noteFunding Information:
We are grateful to G. Kern, Innsbruck, Austria, for the mdg mice. Plasmids and cell lines were kindly provided by J. Rossert, C.G. Kim, and D. Zipori. The authors wish to thank T. Volk, B. Shilo, and R. Shachar for their helpful reviews of the manuscript and to N. Konstantin for expert editorial assistance. We thank S. Kerief and D. Loeliger for expert technical support. Special thanks to all members of the Zelzer laboratory for advice and suggestions. We thank A. Florentin and the Graphic Design Department of Weizmann Institute of Science for their help with designing the graphic model. This work was supported by grants from Israel Science Foundation grant 499/05, Minerva grant M941, The Leo and Julia Forchheimer Center for Molecular Genetics, The Stanley Chais New Scientist Fund, The Kirk Center for Childhood Cancer and Immunological Disorders, The David and Fela Shapell Family Center for Genetic Disorders Research, The Clore Center for Biological Physics, Benoziyo Institute, NIH grant PO1 DK56246 (to C.J.T.), NICHD grant F32HD057701 (to J.L.G.), and NIAMS grant R01 AR055640 (to R.S.). E.Z. is the incumbent of the Martha S. Sagon Career Development Chair.