Treatment with N- and C-Terminal Peptides of Parathyroid Hormone-Related Protein Partly Compensate the Skeletal Abnormalities in IGF-I Deficient Mice

Abstract

Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1–36) and PTHrP (107–111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a , cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1–36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1–36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone.

Parathyroid hormone-related protein (107-111) improves the bone regeneration potential of gelatin–glutaraldehyde biopolymer-coated hydroxyapatite

“…This was not surprising, considering the ability of this peptide to reduce the number of trabecular osteoclasts when administered subcutaneously, as recently reported [45], and the observed increase in OPG/RANKL mRNA ratio induced by PTHrP (107-111)-loaded HA Glu scaffolds in osteoblast cultures in this work. In fact, PTHrP (107-139) has consistently been shown to display anti-resorptive features in rodents [17,[20][21][22], apparently by interacting with osteoclasts directly or indirectly through targeting osteoblasts [19,23,26,28].…”

Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies

“…Results from an early study in ovariectomized rats indicate that daily s.c. injection of osteostatin (18 lg/kg) for 13 days restored the decreased femoral bone mass, apparently through its effect on cortical bone [61]. Consistent with these early findings, we recently found that a clear osteogenic effect was achieved in the long bones of normal mice by administering for 2 weeks a high dose of osteostatin displaying anti-resorptive features [29]. Interestingly, the bone anabolic activity of osteostatin-similar but not identical to that of PTHrP (1-36) using a similar administration regime-was apparent in trabecular bone of mice with IGF-I deficiency and a low bone resorption status [29].…”

“…In particular, the increase in the number of osteoblasts induced by this PTHrP peptide observed in these models seemed to be a consequence of both an increased osteogenic capacity-associated with decreased adipogenesisof the bone marrow and a diminished osteoblast apoptosis [31,56,57]. Our group also recently demonstrated that this type of short treatment of young adult mice with the same PTHrP analog was efficient for improving various cortical bone parameters, but this was not observed in Igf1-null mice, similar to what occurs for the PTH anabolic action [29]. 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.…”

“…PTHrP, by interacting with the PTH1R, augments IGF-I synthesis, which may be responsible for some of the anabolic actions of PTHrP in osteoblasts [27][28][29]. Moreover, PTHrP has also recently been shown to modulate various components (both activators and inhibitors) of the canonical Wnt/b-catenin pathway, an important modulator of osteoblast function [30], promoting its activation [31][32][33].…”

Local delivery of parathyroid hormone-related protein-derived peptides coated onto a hydroxyapatite-based implant enhances bone regeneration in old and diabetic rats

“…11 Interestingly in this regard, systemic administration of N-or C-terminal PTHrP peptides has been reported to reverse at least in part the alterations in bone structure and/or osteoblast differentiation and function in a well characterized type 1 DM mouse model and in Igf1-null mice. [12][13][14] Moreover, we previously showed that osteostatin coating onto various implant types of ceramics or even porous titaniums accelerates healing of critical and non-critical bone defects in the long bones of adult rabbits and rats. 15,16 These observations prompted us to evaluate and compare the efficacy of different PTHrP peptides to promote bone regeneration in a combined aging and DM scenario using a well characterized diabetic model.…”