Date Published: January 25, 2019
Publisher: Public Library of Science
Author(s): Joseph D. Gardinier, Conor Daly-Seiler, Niloufar Rostami, Siddharth Kundal, Chunbin Zhang, Damian Christopher Genetos.
Exercise and physical activity are critical to maintain bone mass and strength throughout life. Both exercise and physical activity subject bone to a unique combination of stimuli in the forms of dynamic loading and a systemic increase in parathyroid hormone (PTH). Although dynamic loading is considered to be the primary osteogenic stimuli, the influence of increasing PTH levels remains unclear. We hypothesize that activation of the PTH/PTH-related peptide type 1 receptor (PPR) along the osteoblast lineage facilitates bone formation and improved mechanical properties in response to exercise. To test this hypothesis, conditional PPR-knockout mice (PPRcKO) were generated in which PPR expression was deleted along the osteoblast lineage under the osterix promoter. At 8-weeks of age, both PPRfl/fl and PPRcKO mice were subjected to treadmill running or sedentary conditions for 5-weeks. Under sedentary conditions, PPRcKO mice displayed significantly less bone mass as well as smaller structural-level strength (yield-load and ultimate load), while tissue level properties were largely unaffected. However, PPRcKO mice exposed to exercise displayed significantly less structural-level and tissue-level mechanical properties when compared to exercised PPRfl/fl mice. Overall, these data demonstrate that PPR expression along the osteoblast lineage is essential for exercise to improve the mechanical properties of cortical bone. Furthermore, the influence of PPR activation on material properties is unique to exercise and not during normal growth and development.
The incidence and economic burden of osteoporotic fractures continues to grow each year. Maintaining bone mass and strength are critical to preventing osteoporosis and reducing fracture risk throughout life. Exercise and physical activity throughout life are key preventative measures recommended by the National Osteoporosis Foundation to reduce fracture risk. Understanding the underlying mechanisms by which exercise regulates bone metabolism is essential to developing therapeutic strategies that reduce risk of osteoporosis and fracture.
The present findings demonstrate that PTH signaling during exercise has a unique role in bone adaptation that is mediated through PPR activation along the osteoblast lineage. By deleting PPR expression in osteoblasts and osteocytes, we were able to prevent exercise from modifying the material properties of bone based on measured changes in tissue-level mechanical properties. Furthermore, changes in tissue-level mechanical properties through PPR expression was unique to exercise and not growth or development under sedentary conditions. The activation of PPR during exercise is likely in response to either PTH released by the parathyroid gland or PTHrP released locally. In particular, exercise significantly increases osteocytes’ production of PTHrP, which in turn would activate PPR in an autocrine/paracrine fashion. However, Chow et al demonstrated in rats that removing the parathyroid glands abrogates both trabecular and cortical bone formation in response to exogenous loading, suggesting that systemic levels of PTH plays a larger role than the local expression of PTHrP in regulating the sensitivity of bone to dynamic loading. In either case, our findings argue that direct activation of the PPR in bone is responsible for modifying the material properties of bone during exercise. In our previous work, inhibition of PPR activation during exercise by way of treating with PTH(7–34) inhibited trabecular bone growth as well as structural-level mechanical properties, but failed to prevent gains in tissue-level mechanical properties. The inability to inhibit changes to tissue-level properties similar to this study is most likely due to the limited capacity of PTH(7–34) to inhibit PPR activation along with its potential to activate anabolic pathways through β-arrestin. Thus, by deleting PPR expression genetically, the present study demonstrates for the first time that PTH signaling during exercise also plays a critical role in regulating tissue-level mechanical properties.