Abstract
Osteoporosis is a common disorder characterized by compromised bone strength that predisposes patients to increased fracture risk. Parathyroid hormone related protein (PTHrP) is one of the candidates for clinical osteoporosis treatment. In this study, GST Gene Fusion System was used to express recombinant human PTHrP (hPTHrP) 1-34 and 1-84. To determine whether the recombinant hPTHrP1-34 and 1-84 can enhance renal calcium reabsorption and promote bone formation, we examined effects of recombinant hPTHrP1-34 and 1-84 on osteogenic lineage commitment in a primary bone marrow cell culture system and on osteoporosis treatment. Results revealed that both of recombinant hPTHrP1-34 and 1-84 increased colony formation and osteogenic cell differentiation and mineralization in vitro; however, the effect of recombinant hPTHrP1-84 is a little stronger than that of hPTHrP1-34. Next, ovariectomy was used to construct osteoporosis animal model (OVX) to test activities of these two recombinants in vivo. HPTHrP1-84 administration elevated serum calcium by up-regulating the expression of renal calcium transporters, which resulted in stimulation of osteoblastic bone formation. These factors contributed to augmented bone mass in hPTHrP1-84 treated OVX mice but did not affect bone resorption. There was no obvious bone mass alteration in hPTHrP1-34 treated OVX mice, which may be, at least partly, associated with shorter half-life of hPTHrP1-34 compared to hPTHrP1-84 in vivo. This study implies that recombinant hPTHrP1-84 is more effective than hPTHrP1-34 to enhance renal calcium reabsorption and to stimulate bone formation in vivo.
Highlights
Osteoporosis is a common disorder characterized by compromised bone strength that predisposes patients to increased fracture risk
Consistent with these results, our data showed that treatment with hPTHrP1-34 and 1-84 caused a significant increase in colony formation and osteogenic cell differentiation and mineralization in primary bone marrow cultures compared with control cultures
We found that treatment with PTHrP1-84 resulted in a slightly increase in total colony forming units fibroblastic (CFU-f) number and alkaline phosphatase (ALP)-positive CFU-f number compared with PTHrP1-34 treated cultures
Summary
Osteoporosis is a common disorder characterized by compromised bone strength that predisposes patients to increased fracture risk. It arises, in part, as a consequence of bone loss secondary to an imbalance between the processes of bone resorption and formation during the normal bone remodeling cycle [1]. A variety of drugs are available for osteoporosis treatment, including antiresorptive and anabolic agents. Antiresorptive drugs treating osteoporosis, act by inhibiting osteoclast activity and slowing the rate of bone remodeling, rather than by rebuilding bone. Anabolic agents reduce fracture incidence by directly stimulating bone formation in addition to increasing bone mass. The only anabolic agent currently being approved in the United States for osteoporosis treatment, parathyroid hormone 1-34
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