Tissue-engineered Bone Responds to Systemic PTH Administration: New Insights into the Anabolic Action of PTH

PTH exerts both catabolic and anabolic actions in bone, depending on the dosing regimen. High doses promote bone resorption, whereas intermittent, low doses increase bone mass. Since the cellular and molecular mechanisms controlling the anabolic action of PTH in bone remain unknown, suitable model systems are required to better understand this effect. Objective: To characterize a novel approach to elucidate mechanisms of PTH action in tissue-engineered bone. Methods: Ectopic ossicles were generated in immunocompromised mice by the differentiation of transplanted bone marrow stromal cells (BMSCs) seeded in gelatin scaffolds. Catabolic or anabolic doses of PTH or vehicle were administered subcutaneously. Results: Ossicles from mice treated with catabolic PTH doses (as evidenced by increased serum calcium levels) contained more TRAP+ osteoclasts/mm of bone as compared to vehicle-treated controls (p<0.01). Intermittent PTH treatment stimulated a dramatic anabolic response in the ossicles, especially in trabecular bone. Microcomputed tomographic and histomorphometric analyses revealed marked increases in percent bone volume (48 ± 2.0 % (PTH) vs. 30 ± 3.0 % (vehicle), p<0.01) and percent trabecular bone area (37 ± 7.4 % (PTH) vs. 14 ± 2.0 % (vehicle), p<0.01), respectively, in ossicles exposed to PTH. Interestingly, no gain in vertebral trabecular bone was found in host mice that displayed substantial increases in ectopic ossicle bone in response to PTH. Conclusion: BMSC-derived, tissue-engineered bone responds to systemically administered PTH. This study suggests that the anabolic response to PTH is more likely to occur in bone that is in a growth or high turnover state like the developing ossicles as compared to more mature vertebral bone. This model offers an innovative approach to elucidate basic mechanisms of PTH actions on skeletal physiology in health and disease with potential applications in bone regeneration, cell signaling and cellular interactions in the bone marrow microenvironment. NIH DK53904 and DE13835.