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Stem cell antigen‐1 positive cell‐based systemic human growth hormone gene transfer strategy increases endosteal bone resorption and bone loss in mice
Author(s) -
Hall Susan L.,
Chen ShinTai,
Wergedal Jon E.,
Gridley Daila S.,
Mohan Subburaman,
Lau K.H. William
Publication year - 2011
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1542
Subject(s) - endocrinology , bone resorption , medicine , bone marrow , resorption , chemistry , growth factor , biology , receptor
Abstract 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 micro‐computed 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 < 0.002) in hGH recipient mice. Femoral trabecular bone volume of the hGH mice was significantly reduced by 35% ( p < 0.002). The hGH mice also had decreased trabecular number (by 26%; p < 0.0001), increased trabecular separation (by 38%; p < 0.0002) and reduced trabecular connectivity density (by 64%; p < 0.001), as well as significantly more osteoclasts (2.5‐fold; p < 0.05) and greater osteoclastic surface per bone surface (2.6‐fold; p < 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 & Sons, Ltd.