Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling
Neha S. Dole,
Courtney M. Mazur,
Claire Acevedo,
Justin P. Lopez,
David A. Monteiro,
Tristan W. Fowler,
Bernd Gludovatz,
Flynn Walsh,
Jenna N. Regan,
Sara Messina,
Daniel S. Evans,
Thomas F. Lang,
Bin Zhang,
Robert O. Ritchie,
Khalid S. Mohammad,
Tamara Alliston
Affiliations
Neha S. Dole
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Courtney M. Mazur
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Claire Acevedo
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Justin P. Lopez
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
David A. Monteiro
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Tristan W. Fowler
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Bernd Gludovatz
Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Flynn Walsh
Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Jenna N. Regan
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Sara Messina
Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Daniel S. Evans
California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA
Thomas F. Lang
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA
Bin Zhang
Department of Genetics & Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Robert O. Ritchie
Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Khalid S. Mohammad
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Tamara Alliston
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy−/−), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.
