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Christopher D Kegelman (1,2), Jennifer C. Coulombe (3), Kelsey M Jordan (1,2), Daniel J. Horan (4), Ling Qin (1), Alexander G Robling (4), Virginia L. Ferguson (3), Teresita M Bellido (4), Joel D Boerckel (1,2)
Journal of Bone and Mineral Research, 35, Issue 1, 2020: 196-210. DOI: 10.1002/jbmr.3876
Transcription Factors, Osteocytes, Molecular Pathways-Remodeling, Genetic Animal Models, Collagen
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 8 kb‐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.
Dragonfly was used for segmentation of bone types and osteocyte lacunae regions.
(1) Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.
(2) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
(3) Department of Mechanical Engineering, University of Colorado, Boulder, CO, USA.
(4) Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
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