Two decades after signals controlling bone length were discovered, the endogenous ligands determining bone width remain unknown. We show that postnatal establishment of normal bone width in mice, as mediated by bone-forming activity of the periosteum, requires BMP signaling at the innermost layer of the periosteal niche. This developmental signaling center becomes quiescent during adult life. Its reactivation however, is necessary for periosteal growth, enhanced bone strength, and accelerated fracture repair in response to bone-anabolic therapies used in clinical orthopedic settings. Although many BMPs are expressed in bone, periosteal BMP signaling and bone formation require only Bmp2 in the Prx1-Cre lineage. Mechanistically, BMP2 functions downstream of Lrp5/6 pathway to activate a conserved regulatory element upstream of Sp7 via recruitment of Smad1 and Grhl3. Consistent with our findings, human variants of BMP2 and GRHL3 are associated with increased risk of fractures.
The DiscoverEHR human dataset is published and publicly available at http://www.discovehrshare.com. Using search terms 'BMP2' and 'GRHL3' and a Bonferroni significance threshold of P < 1.86e-7 for 268,192 association results, we observed three significant associations for BMP2 and six significant associations for GRHL3.Mouse limb bud ChIP-sequencing data are available through ArrayExpress website https://www.ebi.ac.uk/arrayexpress and accession #E-MTAB-7652.
Mouse Limb Bud Bcl-9 Chromatin Immunoprecipitation and SequencingArray Express, E-MTAB-7652.
- Vicki Rosen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: In vivo experiments were performed in compliance with the Guide for the Care and Use of Laboratory Animals and were approved by the Harvard Medical Area Institutional Animal Care and Use Committee (protocol #04043 to Vicki Rosen).
- Clifford J Rosen, Maine Medical Center Research Institute, United States
© 2019, Salazar et al.
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