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

doi:10.1016/j.celrep.2017.10.115

Abstract

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.

Highlights

Bone fragility is determined by bone mass and quality
Pharmacologic Inhibition of transforming growth factor beta (TGF-b) Signaling Dysregulates perilacunar/canalicular remodeling (PLR) We previously showed that pharmacologic inhibition of the TGF-b-receptor I (TbRI) kinase using SD-208 increases trabecular bone mass through stimulating osteoblastic bone formation and repressing osteoclastic resorption (Mohammad et al, 2009)
To investigate the role of TGF-b signaling in osteocytes, the most abundant bone cells in cortical bone (Franz-Odendaal et al, 2006), we examined histologic and molecular outcomes of osteocyte-mediated PLR in mice treated with SD-208

Summary

Graphical Abstract

Resistance to fracture requires healthy bone mass and quality. The cellular mechanisms regulating bone quality are unclear. Dole et al show that osteocyte-intrinsic TGF-b signaling maintains bone quality through perilacunar/canalicular remodeling. Osteocytes mediate perilacunar/ canalicular remodeling and osteoclastdirected remodeling to cooperatively maintain bone quality and mass and prevent fragility. Highlights d TGF-b is an osteocyte-intrinsic regulator of perilacunar/ canalicular remodeling (PLR). D Osteocytes actively maintain bone quality through regulated control of PLR d Osteocytic PLR is the cellular mechanism by which TGF-b controls bone quality d Defects in PLR cause severe bone fragility, even when bone mass is normal.

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INTRODUCTION

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EXPERIMENTAL PROCEDURES