PTH Signaling During Exercise Contributes to Bone Adaptation

Abstract

Improving the structural integrity of bone reduces fracture risk and development of osteoporosis later in life. Exercise can increase the mechanical properties of bone, and this increase is often attributed to the dynamic loading created during exercise. However, the increase in systemic PTH levels during exercise gives reason to hypothesize that PTH signaling also regulates bone adaptation in response to exercise. Therefore, the first aim of this study was to establish the impact PTH signaling has on bone adaptation during exercise by inhibiting PTH signaling with PTH(7-34) and the second aim was to determine if increasing PTH levels during exercise with PTH(1-34) can augment bone adaptation. Thirty minutes after a single bout of running on a treadmill, mice exhibited a two-fold increase in systemic PTH levels. Under the same exercise regimen, the influence of PTH signaling on bone adaptation during exercise was then evaluated in mice after 21 consecutive days of exercise and treatment with PTH(7-34), PTH(1-34), or vehicle. Exercise alone caused a significant increase in trabecular bone volume with adaptation to a more plate-like structure, which was inhibited with PTH(7-34) during exercise. Changes in structural and tissue-level mechanical properties during exercise occurred in the absence of significant changes to cortical bone geometry. Inhibition of PTH signaling during exercise attenuated the changes in structural-level mechanical properties, but not tissue-level properties. Enhanced PTH signaling during exercise with PTH(1-34) increased trabecular and cortical bone volume, but had little effect on the structural and tissue-level mechanical properties compared to exercise alone. Our study is the first to demonstrate that bone adaptation during exercise is not only a function of the dynamic loading, but also PTH release, and that PTH signaling contributes differently at the structural and tissue-levels.

Overexpression of Gα11 in Osteoblast Lineage Cells Suppresses the Osteoanabolic Response to Intermittent PTH and Exercise

“…The differences in response to iPTH and exercise in G 11 -Tg mice suggest that factors other than PTH were regulating exercise-induced decreases in osteoclasts, and these were not affected by increased Ga 11 expression in osteoblasts. Alternatively, if PTH mediates Previous reports have demonstrated that both iPTH and mechanical strain increase bone formation, but add bone in different magnitudes [9,19]. Consistent with these previous results, the iPTH treatment in this study resulted in significantly greater bone gain than changes in mechanical loading, whereas exercise only slightly increased cortical bone volume and did not increase peak load in WT mice.…”

“…It has been previously shown that mice with constitutively active Ga q in osteoblasts lack a skeletal response to iPTH [12]. Additionally, Gardinier et al recently proposed that PTH signaling is important for bone adaptation during exercise [9]. Therefore, we employed our transgenic mice overexpressing normal Ga 11 to evaluate the influence of elevated Ga 11 on responses to these osteoanabolic regimens, presumably through the actions of PTH, and investigated their effects on altering bone structure, strength, and cellularity.…”

“…P2Y purinergic receptors, which are mostly coupled to Ga q/11 G proteins, are considered the key molecular targets involved in bone mechanotransduction, such as responses to ultrasound and mechanical stress [7,8]. Furthermore, a recent report by Gardinier et al demonstrated that PTH release during exercise contributes to bone adaptation [9]. Collectively, these findings illustrate that GPCR signaling can mediate the effects of osteoanabolic stimuli.…”

Serum sclerostin decreases following 12months of resistance- or jump-training in men with low bone mass

“…In addition to mechanical loading, exercise causes changes in systemic and local hormone concentrations, which might facilitate local skeletal adaptation to increased mechanical loading [14]. For example, PTH released during exercise controls osteocyte gene expression [29], and PTH signaling is associated with increased bone formation and improved structural and material properties [29]. Exercise also increases circulating IGF-I, the source of which is the liver or extrahepatic tissues.…”

PTH signaling mediates perilacunar remodeling during exercise

“…However, there is limited understanding of how exercise influences the mechanical properties of bone, given that increased mineral content or bone quantity does not always translate into improved mechanical function (Hui et al, 1988). To this end, animal studies have identified structural and tissue-level mechanical properties that increase during various forms of exercise, such as swimming, jumping, voluntary running in a cage wheel or running on a treadmill (Gardinier et al, 2015; Hoshi et al, 1998; Huang et al, 2003; Iwamoto et al, 2004; Iwamoto et al, 1999; Kohn et al, 2009). For example, young adult mice running on a treadmill consistently exhibit increased structural and tissue-level properties, such as post-yield properties of the tibia (Gardinier et al, 2015; Hoshi et al, 1998; McNerny et al, 2015; Wallace et al, 2010; Wallace et al, 2009).…”