Abstract
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.
Highlights
Osteoporosis is a primary public health problem listed by the World Health Organization (WHO) [1]
PTHG2 was a glycosylated derivative obtained by acetylglucosamine modification of PTH (1-34) N-terminal serine (Figure 1(a))
By using some in vitro experiments, we found that PTHG2 could promote bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation and inhibit BMSC adipogenic differentiation
Summary
Osteoporosis is a primary public health problem listed by the World Health Organization (WHO) [1]. Imbalance of BMSC osteogenic and adipogenic differentiation in both age-related or postmenopausal osteoporosis has been regarded as a major risk factor [2,3,4]. Current clinical treatment of osteoporosis is aimed at recovering a normal bone metabolic balance [5, 6]. BMSCs are derived from bone marrow, self-renewal, and multipotential progenitor cells of osteoblasts and adipocytes in appropriate conditions [7, 8]. The balance of adipoosteogenic differentiation is under a precise control of both biological and mechanical factors. Under aging or pathological conditions like osteoporosis, BMSCs experience differentiation shift from osteoblasts to adipocytes which leads to adipocytes accumulation, aberrant skeletal architecture, and elevated fracture risk [9,10,11]
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