Browsing by Author "Boerckel, Joel D."

Now showing 1 - 4 of 4
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    Editorial Peer Reviewers as Shepherds, Rather Than Gatekeepers
    (Wiley, 2021) Boerckel, Joel D.; Plotkin, Lilian I.; Sims, Natalie A.; Anatomy, Cell Biology and Physiology, School of Medicine
    The journals of the American Society for Bone and Mineral Research (the Journal of Bone and Mineral Research [JBMR] and its sister journal JBMR Plus) recognize peer review, whether pre- or post-publication, as an essential guard of scientific integrity and rigor that shapes academic discourse in our field. In this Perspective, we present a vision and philosophy of peer review in a rapidly changing publishing landscape. We emphasize the importance of journal peer reviewers as active players in shaping collegial behavior in the musculoskeletal research community and provide information about benefits and resources available for reviewers and reviewers-in-training. Publishing is becoming increasingly transparent, bringing benefits to authors, to reviewers, and to the scientific community at large. We discuss new initiatives such as transparent peer review and preprint servers, the ways they are changing scientific publishing, and how JBMR is responding to broaden the impact of musculoskeletal research. We emphasize the need to change any perception of peer reviewers as gatekeepers to viewing them as shepherds, who partner with authors and editors in the publishing endeavor. Promoting access, transparency, and collegiality in the way we assess science in our community will elevate its quality, clarify its communication, and increase its societal impact. © 2021 American Society for Bone and Mineral Research (ASBMR).
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    Effects of Bone Morphogenetic Protein-2 on Neovascularization During Large Bone Defect Regeneration
    (Mary Ann Liebert, Inc., 2019-12) Pearson, Hope B.; Mason, Devon E.; Kegelman, Christopher D.; Zhao, Liming; Dawahare, James H.; Kacena, Melissa A.; Boerckel, Joel D.; Orthopaedic Surgery, School of Medicine
    Insufficient blood vessel supply is a primary limiting factor for regenerative approaches to large bone defect repair. Recombinant bone morphogenetic protein-2 (BMP-2) delivery induces robust bone formation and has been observed to enhance neovascularization, but whether the angiogenic effects of BMP-2 are due to direct endothelial cell stimulation or due to indirect paracrine signaling remain unclear. In this study, we evaluated the effects of BMP-2 delivery on vascularized bone regeneration and tested whether BMP-2 induces neovascularization directly or indirectly. We found that delivery of BMP-2 (5 μg) enhanced both bone formation and neovascularization in critically sized (8 mm) rat femoral bone defects; however, BMP-2 did not directly stimulate angiogenesis in vitro. In contrast, conditioned medium from both mesenchymal progenitor cells and osteoblasts induced endothelial cell migration in vitro, suggesting a paracrine mechanism of BMP-2 action. Consistent with this inference, codelivery of BMP-2 with endothelial colony forming cells to a heterotopic site, distant from the skeletal stem cell-rich bone marrow niche, induced ossification but had no effect on neovascularization. Taken together, these data suggest that paracrine activation of osteoprogenitor cells is an important contributor to neovascularization during BMP-2-mediated bone regeneration. Impact Statement In this study, we show that bone morphogenetic protein-2 (BMP-2) robustly induces neovascularization during tissue-engineered large bone defect regeneration, and we found that BMP-2 induced angiogenesis, in part, through paracrine signaling from osteoprogenitor cells.
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    Skeletal cell YAP and TAZ combinatorially promote bone development
    (Federation of American Societies for Experimental Biology, 2018-05) Kegelman, Christopher D.; Mason, Devon E.; Dawahare, James H.; Horan, Daniel J.; Vigil, Genevieve D.; Howard, Scott S.; Robling, Alexander G.; Bellido, Teresita M.; Boerckel, Joel D.; Anatomy and Cell Biology, IU School of Medicine
    The functions of the paralogous transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in bone are controversial. Each has been observed to promote or inhibit osteogenesis in vitro, with reports of both equivalent and divergent functions. Their combinatorial roles in bone physiology are unknown. We report that combinatorial YAP/TAZ deletion from skeletal lineage cells, using Osterix-Cre, caused an osteogenesis imperfecta-like phenotype with severity dependent on allele dose and greater phenotypic expressivity with homozygous TAZ vs. YAP ablation. YAP/TAZ deletion decreased bone accrual and reduced intrinsic bone material properties through impaired collagen content and organization. These structural and material defects produced spontaneous fractures, particularly in mice with homozygous TAZ deletion and caused neonatal lethality in dual homozygous knockouts. At the cellular level in vivo, YAP/TAZ ablation reduced osteoblast activity and increased osteoclast activity, in an allele dose-dependent manner, impairing bone accrual and remodeling. Transcriptionally, YAP/TAZ deletion and small-molecule inhibition of YAP/TAZ interaction with the transcriptional coeffector TEAD reduced osteogenic and collagen-related gene expression, both in vivo and in vitro. These data demonstrate that YAP and TAZ combinatorially promote bone development through regulation of osteoblast activity, matrix quality, and osteoclastic remodeling.-Kegelman, C. D., Mason, D. E., Dawahare, J. H., Horan, D. J., Vigil, G. D., Howard, S. S., Robling, A. G., Bellido, T. M., Boerckel, J. D. Skeletal cell YAP and TAZ combinatorially promote bone development.
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    YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling
    (Wiley Periodicals, Inc., 2020-01) Kegelman, Christopher D.; Coulombe, Jennifer C.; Jordan, Kelsey M.; Horan, Daniel J.; Qin, Ling; Robling, Alexander G.; Ferguson, Virginia L.; Bellido, Teresita M.; Boerckel, Joel D.; Anatomy and Cell Biology, School of Medicine
    Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility.