Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor

Delgado‐Calle, Jesús; Tu, Xiaolin; Pacheco‐Costa, Rafael; McAndrews, Kevin; Edwards, Rachel; Pellegrini, G; Kuhlenschmidt, Kali; Olivos, Naomie; Robling, Alexander G.; Peacock, Munro; Plotkin, Lilian I.; Bellido, Teresita

doi:10.1002/jbmr.3011

Cited by 95 publications

(107 citation statements)

References 53 publications

(173 reference statements)

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“…(35,51) We used a breeding strategy that generated YAP/TAZ allele dosage-dependent DMP1-conditional knockouts. (35,51) We used a breeding strategy that generated YAP/TAZ allele dosage-dependent DMP1-conditional knockouts.…”

Section: Dmp1-cre Conditionally Ablates Yap and Taz Primarily In Ostementioning

confidence: 99%

YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling

Kegelman

Coulombe

Jordan

et al. 2019

Journal of Bone and Mineral Research

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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.

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Section: Dmp1-cre Conditionally Ablates Yap and Taz Primarily In Ostementioning

confidence: 99%

YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling

Kegelman

Coulombe

Jordan

et al. 2019

Journal of Bone and Mineral Research

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“…Surprisingly, cortical osteoblasts (CO) isolated from same animals, were “insensitive” to microgravity. Furthermore, mice with conditional deletion of PTHR in osteocytes were resistant to bone gain induced by axial ulna loading, demonstrating the need of an intact PTH-PTHrP-PTHR axis for proper skelatal mechano-transduction (37). …”

Section: Osteocytes’ Mechano-sensationmentioning

confidence: 99%

Osteocyte Mechanobiology

Uda

Azab

Sun

et al. 2017

Curr Osteoporos Rep

161

132

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Purpose of this Review Over the past decades, osteocytes have emerged as mechano-sensors of bone and master regulators of bone homeostasis. This article summarizes latest research and progress made in understanding osteocyte mechanobiology and critically reviews tools currently available to study these cells. Recent Findings Whereas increased mechanical forces promote bone formation, decrease loading is always associated with bone loss and skeletal fragility. Recent studies identified cilia, integrins, calcium channels and G-protein coupled receptors as important sensors of mechanical forces and Ca2+ and cAMP signaling as key effectors. Among transcripts regulated by mechanical forces, sclerostin and RANKL have emerged as potential therapeutic targets for disuse-induced bone loss. Summary In this paper we review the mechanisms by which osteocytes perceive and transduce mechanical cues and the models available to study mechano-transduction. Future directions of the field are also discussed.

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“…Constitutive activation (ca) of the PTH receptor 1 (PTH1R) signaling in Ots (caPTH1R Ot mice) is sufficient to increase bone mass and the rate of bone remodeling (7). Furthermore, the expression of the PTH1R in Ots is required for the full anabolic response to daily injections of PTH (8). Ots are major producers of RANKL (9, 10), and more recent studies demonstrated that resorption induced by PTH in the adult skeleton requires direct regulation of the Rankl gene in Ots (11).…”

mentioning

confidence: 99%

MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production

et al. 2018

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Parathyroid hormone (PTH) affects the skeleton by acting on osteocytes (Ots) in bone through yet unclear mechanisms. We report that matrix metalloproteinase 14 (MMP14) expression/activity are increased in bones from mice with genetic constitutive activation (ca) of the PTH receptor 1 (PTH1R) in Ots (caPTH1R) and in bones from mice exposed to elevated PTH levels but not in mice lacking [conditional knockout (cKO)] the PTH1R in Ots (cKOPTH1R). Furthermore, PTH upregulates MMP14 in human bone cultures and in Ot-enriched bones from floxed control mice but not from cKOPTH1R mice. MMP14 activity increases soluble receptor activator of NF-κΒ ligand production, which in turn, stimulates osteoclast differentiation and resorption. Pharmacologic inhibition of MMP14 activity reduced the high bone remodeling exhibited by caPTH1R mice or induced by chronic PTH elevation and decreased bone resorption but allowed full stimulation of bone formation induced by PTH injections, thereby potentiating bone gain. Thus, MMP14 is a new member of the intricate gene network activated in Ots by PTH1R signaling that can be targeted to adjust the skeletal responses to PTH in favor of bone preservation.-Delgado-Calle, J., Hancock, B., Likine, E. F., Sato, A. Y., McAndrews, K., Sanudo, C., Bruzzaniti, A., Riancho, J. A., Tonra, J. R., Bellido, T. MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production.

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Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor

Cited by 95 publications

References 53 publications

YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling

YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling

Osteocyte Mechanobiology

MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production

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