Androgens Inhibit the Osteogenic Response to Mechanical Loading in Adult Male Mice

Sinnesael, Mieke; Laurent, Michaël; Jardí, Ferran; Dubois, Vanessa; Deboel, Ludo; Delisser, Peter J; Behets, Geert J.; D’Haese, Patrick C.; Carmeliet, Geert; Claessens, Frank; Vanderschueren, Dirk

doi:10.1210/en.2014-1673

Cited by 35 publications

(32 citation statements)

References 63 publications

(66 reference statements)

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“…However, once sclerostin had been shown to be expressed in osteocytes [9], Robling et al [16] convincingly demonstrated that one potentially important mechanism by which mechanical loading controls osteocyte activity is by regulating sclerostin expression. His demonstration that loading the mouse ulna down regulates sclerostin expression has been reproduced in a variety of experimental loading models [17], [18], [19], [20], [21], [22], [23] (Fig. 1).…”

Section: Introductionmentioning

confidence: 88%

Sclerostin's role in bone's adaptive response to mechanical loading

Galea

Lanyon

Price

2017

Bone

118

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Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis.

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Section: Introductionmentioning

confidence: 88%

Sclerostin's role in bone's adaptive response to mechanical loading

Galea

Lanyon

Price

2017

Bone

118

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“…They injected FITC-labeled bovine serum albumin tracer into rats’ tibia during loading and demonstrated that the load-induced solute transport around osteocyte was enhanced in ovariectomized animals (48). Another study reported that androgens inhibits osteogenic responses to mechanical loading in adult male mice (49) demonstrating a close relationship between sex hormones and skeletal mechanobiology.…”

Section: Osteocytes’ Mechano-transductionmentioning

confidence: 97%

Osteocyte Mechanobiology

Uda

Azab

Sun

et al. 2017

Curr Osteoporos Rep

159

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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“…Thus, Callewaert et al[45] found that loading induced significantly more periosteal bone formation in male androgen receptor knock out (ARKO) as compared with WT mice and had a stronger inhibitory effect on sclerostin expression in ARKO vs WT mice. In a subsequent study, Sinnesael et al [46] found that testosterone treatment of orchiectomized mice increased the number of sclerostin-positive osteocytes. In contrast to these findings, Di Nisio et al [29] found that dihydrotesterone (DHT) decreased sclerostin expression in cultured human osteocytes, suggesting that the in vitro (direct) effects of androgens may differ from their in vivo (perhaps indirect) effects on sclerostin production.…”

Section: Hormonal Regulation Of Sclerostinmentioning

confidence: 99%

Hormonal and systemic regulation of sclerostin

Drake

Khosla

2017

Bone

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The Wnt/β-catenin signaling pathway plays an essential role in osteoblast biology. Sclerostin is a soluble antagonist of Wnt/β-catenin signaling secreted primarily by osteocytes. Current evidence indicates that sclerostin likely functions as a local/paracrine regulator of bone metabolism rather than as an endocrine hormone. Nonetheless, circulating sclerostin levels in humans often reflect changes in the bone microenvironment, although there may be exceptions to this observation. Using existing assays, circulating sclerostin levels have been shown to be altered in response to both hormonal stimuli and across a variety of normal physiological and pathophysiological conditions. In both rodents and humans, parathyroid hormone provided either intermittently or continuously suppresses sclerostin levels. Likewise, most evidence from both human and animal studies supports a suppressive effect of estrogen on sclerostin levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have in general shown less consistent findings or have provided associations rather than direct interventional information, with the exception of mechanosensory studies which have consistently demonstrated increased sclerostin levels with skeletal unloading, and conversely decreases in sclerostin with enhanced skeletal loading. Herein, we will review the existent literature on both hormonal and non-hormonal/systemic factors which have been studied for their impact on sclerostin regulation.

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Androgens Inhibit the Osteogenic Response to Mechanical Loading in Adult Male Mice

Cited by 35 publications

References 63 publications

Sclerostin's role in bone's adaptive response to mechanical loading

Sclerostin's role in bone's adaptive response to mechanical loading

Osteocyte Mechanobiology

Hormonal and systemic regulation of sclerostin

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