Osteogenic growth peptide effects on primary human osteoblast cultures: potential relevance for the treatment of glucocorticoid-induced osteoporosis.
The osteogenic growth peptide (OGP) is a naturally occurring tetradecapeptide that has attracted considerable clinical interest as a bone anabolic agent and hematopoietic stimulator. In vivo studies on animals have demonstrated that the synthetic peptide OGP (10-14), reproducing the OGP C-terminal active portion [H-Tyr-Gly-Phe-Gly-Gly-OH] increases bone formation, trabecular bone density and fracture healing. In vitro studies performed on cellular systems based on osteoblastic-like cell lines or mouse stromal cells, have demonstrated that OGP (10-14) increases osteoblast proliferation, alkaline phosphatase (ALKP) activity and matrix synthesis and mineralization. In view of a potential application of OGP (10-14) in clinical therapy, we have tested different concentrations of OGP (10-14) on primary human osteoblast (hOB) cultures. We have observed significant increases of hOB proliferation (+35%), ALKP activity (+60%), osteocalcin secretion (+50%), and mineralized nodules formation (+49%). Our experimental model based on mature hOBs was used to investigate if OGP (10-14) could prevent the effects on bone loss induced by sustained glucocorticoid (GC) treatments. A strong decrease in bone formation has been attributed to the effects of GCs on osteoblastogenesis and osteocyte apoptosis, while an increase in bone resorption was due to a transient osteoblastic stimulation, mediated by the OPG/RANKL/RANK system, of osteoclasts recruitment and activation. Moreover, GCs act on hOBs decreasing the release of osteoprotegerin (OPG) a regulator of the RANKL/RANK interaction. Here, we provide evidences that OGP (10-14) inhibits hOB apoptosis induced by an excess of dexamethasone (-48% of apoptotic cells). Furthermore, we show that OGP (10-14) can increase OPG secretion (+20%) and can restore the altered expression of OPG induced by GCs to physiological levels. Our results support the employment of OGP (10-14) in clinical trials addressed to the treatment of different bone remodeling alterations including the GC-induced osteoporosis.
Spreafico
Adriano
A
Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, University of Siena, 53100 Siena, Italy. spreafico@unisi.it
Frediani
Bruno
B
Capperucci
Caterina
C
Leonini
Alessandra
A
Gambera
Dario
D
Ferrata
Paolo
P
Rosini
Sergio
S
Di Stefano
Anna
A
Galeazzi
Mauro
M
Marcolongo
Roberto
R
D000368:Aged; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004723:Endorphins / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D004723:Endorphins; D005938:Glucocorticoids; C050198:historphin