Stem cell antigen-1 positive cell-based systemic human growth hormone gene transfer strategy increases endosteal bone resorption and bone loss in mice

摘要

Background The present study assesses the effect of the stem cell antigen-1 positive (Sca-1~+) cell-based human growth hormone (hGH) ex vivo gene transfer strategy on endosteal bone mass in the mouse. Methods Sublethally irradiated recipient mice were transplanted with Sca-1~+ cells transduced with lentiviral vectors expressing hGH or β-galactosidase control genes. Bone parameters were assessed by microcomputed tomography and histomorphometry. Results This hGH strategy drastically increased hGH mRNA levels in bone marrow cells and serum insulin-like growth factor-I (IGF-I) (by nearly 50%, p {L-End} < 0.002) in hGH recipient mice. Femoral trabecular bone volume of the hGH mice was significantly reduced by 35% (p {L-End} < 0.002). The hGH mice also had decreased trabecular number (by 26%; p {L-End} < 0.0001), increased trabecular separation (by 38%; p {L-End} < 0.0002) and reduced trabecular connectivity density (by 64%; p {L-End} < 0.001), as well as significantly more osteoclasts (2.5-fold; p {L-End} < 0.05) and greater osteoclastic surface per bone surface (2.6-fold; p {L-End} < 0.01). Conclusions Targeted expression of hGH in cells of marrow cavity through the Sca-1~+ cell-based gene transfer strategy increased circulating IGF-I and decreased endosteal bone mass through an increase in resorption in recipient mice. These results indicate that high local levels of hGH or IGF-I in the bone marrow microenvironment enhanced resorption, which is consistent with previous findings in transgenic mice with targeted bone IGF-I expression showing that high local IGF-I expression increased bone remodeling, favoring a net bone loss. Thus, GH and/or IGF-I would not be an appropriate transgene for use in this Sca-1~+ cell-based gene transfer strategy to promote endosteal bone formation. Published 2011 John Wiley {L-End} & Sons, Ltd.