Recombinant Human Parathyroid Hormone Related Protein 1-34 and 1-84 and Their Roles in Osteoporosis Treatment

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.

Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(−/−) Mice

“…Since HPTHrP-(1-84) administration resulted in elevated extracellular calcium levels through increasing of renal calcium transport and osteoblastic bone formation without affecting bone resorption [10], we infer that the differences between half-life and functions of diverse PTHrP sequences might explain these diverse findings. Our studies demonstrate that exogenous PTHrP can enhance bone fracture healing in diabetic mice and improve the condition of pancreas islet b cells.…”

“…Furthermore, Plotkin et al found that in sharp contrast to PTH-treated subjects, PTHrP-treated individuals showed significantly reduced levels of bone resorption markers; in their study, 13 postmenopausal estrogen-deficient women were administered a single daily s.c. dose of PTHrP-(1-36) for a 2-week period [9]. Meanwhile, by measuring serum concentrations of hPTHrP- and hPTHrP-(1-84) at different time points after administration, Miao et al found much shorter circulating lifetime for hPTHrP-(1-34) compared with hPTHrP-(1-84), the latter being more effective than the former [10]. These observations indicate that treatment with PTHrP uncouples bone formation from bone resorption, in favor of formation, indicating that PTHrP might be a potent anabolic therapeutic agent for osteoporosis.…”

Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies

“…Another recent study has compared the osteogenic capacity of PTHrP (1-34) and PTHrP (1-84) administered at the same equivalent dose (10 nmol/kg) for 4 weeks to ovariectomized mice. It was shown that the latter peptide was more effective than PTHrP (1-34) to stimulate bone formation, related to its higher circulating lifetime and increased renal calcium reabsorption [58]. A substituted human PTHrP (1-34) analog (abaloparatide, formerly known as BA085) has recently been developed and preclinically tested.…”

Hypoparathyroidism: disease update and new methods of treatment

“…ПТГ(1-84) выпускается в форме шприц-ручки и используется в режи-ме однократных подкожных инъекций в дозах 25, 50, 75 или 100 мкг. Период полувыведения ПТГ(1-84) больше, чем у ПТГ(1-34), что объ-ясняет возможность назначения препарата 1 раз в сутки [47][48][49].…”