PTHG2 Reduces Bone Loss in Ovariectomized Mice by Directing Bone Marrow Mesenchymal Stem Cell Fate

Teriparatide, also known as 1-34 parathyroid hormone (PTH (1-34)), is commonly used for the treatment of osteoporosis in postmenopausal women. But its therapeutic application is restricted by poor metabolic stability, low bioavailability, and rapid clearance. Herein, PTHG2, a glycosylated teriparatide derivative, is designed and synthesized to improve PTH stability and exert more potent antiosteoporosis effect. Surface plasmon resonance (SPR) analysis shows that PTHG2 combines to PTH 1 receptor. Additional acetylglucosamine covalent bonding in the first serine at the N terminal of PTH (1-34) improves stability and increases protein hydrolysis resistance. Intermittent administration of PTHG2 preserves bone quality in ovariectomy- (OVX-) induced osteoporosis mice model, along with increased osteoblastic differentiation and bone formation, and reduced marrow adipogenesis. In vitro, PTHG2 inhibits adipogenic differentiation and promotes osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). For molecular mechanism, PTHG2 directs BMSCs fate through stimulating the cAMP-PKA signaling pathway. Blocking PKA abrogates the pro-osteogenic effect of PTHG2. In conclusion, our study reveals that PTHG2 can accelerate osteogenic differentiation of BMSCs and inhibit adipogenic differentiation of BMSCs and show a better protective effect than PTH (1-34) in the treatment of osteoporosis.

Automated summary

Teriparatide, also known as 1-34 parathyroid hormone, is commonly used for treating osteoporosis in postmenopausal women. However, its therapeutic potential is limited by stability issues and low bioavailability. A glycosylated derivative, PTHG2, was designed to improve stability and anti-osteoporosis effects. In animal models and in vitro experiments, PTHG2 promoted bone formation, inhibited marrow adipogenesis, and directed BMSCs fate through the cAMP-PKA signaling pathway.