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Published on: May 2, 2025
Stem cell antigen-1 positive cell-based systemic human growth hormone gene transfer strategy increases endosteal bone
Susan L Hall1, Shin-Tai Chen, Jon E Wergedal
1Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA, USA. susan.hall1@va.gov
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.
Insights
Gene transfer of human growth hormone (hGH) using Sca-1(+) cells increased IGF-I but decreased bone mass by enhancing resorption. This strategy is not suitable for promoting endosteal bone formation.
Area of Science:
- Biomedical Engineering
- Gene Therapy
- Bone Biology
Background:
- Assessing the efficacy of stem cell antigen-1 positive (Sca-1(+)) cell-based gene transfer for human growth hormone (hGH) delivery.
- Investigating the impact of this strategy on endosteal bone mass in a murine model.
Purpose of the Study:
- To evaluate the effect of Sca-1(+) cell-mediated hGH gene transfer on bone parameters.
- To determine the role of hGH and IGF-I in bone remodeling within the bone marrow microenvironment.
Main Methods:
- Transplantation of Sca-1(+) cells engineered to express hGH or a control gene into sublethally irradiated mice.
- Assessment of bone parameters using micro-computed tomography and histomorphometry.
Main Results:
- Significant increase in hGH mRNA and serum IGF-I levels in hGH-treated mice.
- Marked reduction in femoral trabecular bone volume, number, and connectivity density.
- Increased osteoclast number and surface, indicating enhanced bone resorption.
Conclusions:
- Sca-1(+) cell-based hGH gene transfer elevates circulating IGF-I and reduces endosteal bone mass via increased resorption.
- High local levels of hGH or IGF-I in the bone marrow promote resorption, leading to net bone loss.
- This gene transfer approach is inappropriate for promoting endosteal bone formation due to enhanced bone resorption.
