Loss of the PTH/PTHrP receptor along the osteoblast lineage limits the anabolic response to exercise

Abstract

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.

Physical Activity-Dependent Regulation of Parathyroid Hormone and Calcium-Phosphorous Metabolism

“…Treatment with PTH(1-34) increased both trabecular and cortical bone volume [ 173 ]. PTH signaling through PTHR1 in the cells of the osteoblastic lineage seemed to mediate exercise-dependent PTH-mediated anabolic effects, as demonstrated in mice conditionally KO of PTHR1 in osteoblasts [ 174 ].…”

“…Additionally, 13 weeks of military training, despite the improved bone status (improved site-specific BMD, reduced CTx-I), were unable to induce changes in PTH levels or ionized calcium and PINP [ 208 ]. In mice models, 6-week training programs (power, endurance, combined, or untrained) increased circulating PTH levels, together with downregulation of anti-anabolic factors in the cortical portion of the tibia but only in the power-trained mice [ 174 ].…”

Bone Cells Differentiation: How CFTR Mutations May Rule the Game of Stem Cells Commitment?

“…Parathyroid hormone is the primary calcium metabolism regulating hormone. Osteoblasts are rich in PTH receptors and PTH-related protein receptors (Gardinier et al, 2019). Intermittent PTH injections in rat promotes osteoblast differentiation and bone formation, whereas continuous PTH injection inhibits osteogenesis (Frolik et al, 2003).…”

Interaktion zwischen Muskel und Knochen – ein Wechselspiel zwischen Physik und Biologie

“…Microgravity fast komplett verloren. Der Verlust der PTH1R-Expression in osteogenen Zellen hemmt die Mechanosensitivität, und eine neuere klinische Studie kommt zu dem Ergebnis, dass die Kombination aus mechanischer Stimulation und Teriparatid mit Blick auf den Gewinn an Knochenmasse wesentlich effektiver ist als Teriparatid alleine [47,48]. Aber auch für die "neueren" starken Modulatoren der osteogenen Differenzierung in Entwicklung und Regeneration wurde in jüngster Zeit von unserer Arbeitsgruppe und anderen nachgewiesen, dass sie durch mechanische Reize moduliert werden können [49][50][51][52][53].…”