Local expression of human growth hormone in bone results in impaired mechanical integrity in the skeletal tissue of transgenic mice

Abstract

The effect of local production of human growth hormone on murine cortical bone was investigated using a transgenic mouse model. Femora and humeri from human growth hormone transgenic mice and littermate control mice were obtained, and the geometrical, biomechanical, compositional, and histomorphometric properties of all specimens were determined. The goals were to investigate the effects of local expression of human growth hormone on skeletal integrity, including the functional geometry of long bone and its related structural and mechanical behavior, as well as tissue composition and integrity. As expected, local production of human growth hormone by osteoblasts indeed resulted in longer femora with significantly greater mid-diaphyseal cross-sectional geometry in the transgenic mice (16% increase in cross-sectional area and 29% increase in bending moments of inertia). However, the significant increase in geometry was not associated with a proportional increase in bending stiffness and other structural properties, which suggested that the mechanical properties of the cortical bone tissue may have been inferior. Microspecimen bending tests verified this prediction, given that transgenic cortical bone tissue had significantly lower apparent elastic modulus and ultimate strength (52 and 68%, respectively, of control values). These defects in the whole bone structural and tissue mechanical properties of transgenic specimens were associated with a smaller fraction of ash, larger fractions of woven bone and cartilage islands, and greater porosity in the mid-diaphyseal cortices. These results suggest that local production of human growth hormone by osteoblasts is indeed anabolic for bone, but at the expense of bone tissue integrity.

Bone metabolism in relation to alterations in systemic growth hormone

“…These show that chronic overexpression of GH by osteoblasts, with minimal systemic effects, indeed is anabolic for bone resulting in increased growth and dimensions [82,83]. However, these changes are associated with defects in bone structural and mechanical properties [83]. Studies in mice lacking GHR demonstrate reduced cortical and longitudinal bone growth, decreased bone turnover as well as a markedly reduced bone mineral content (BMC) [84,85].…”

“…In addition, several studies have investigated the effects of local bone overexpression of GH using different promoter systems. These show that chronic overexpression of GH by osteoblasts, with minimal systemic effects, indeed is anabolic for bone resulting in increased growth and dimensions [82,83]. However, these changes are associated with defects in bone structural and mechanical properties [83].…”

Methods for Assessing Bone Quality: A Review

“…In these tests, bending or tensile loads are applied to microbeams (approximately 200 9 200 9 2000 lm) machined from trabecular and cortical bone [20,47,78]. Outcomes include the elastic modulus and ultimate stress.…”

Effects of Growth Hormone Transgene Expression on Vertebrae in a Mouse Model of Osteogenesis Imperfecta

“…This indicates that poor bone material quality in oim/ϩ mice was not improved by hGH expression. The decreased failure stress may be attributable to growth hormone's stimulation of the formation of woven bone, 16,17 in addition to the woven, irregular characteristics already inherent in OI bone. Improved biomechanical performance of the vertebral bones is therefore attributed primarily to the changes in their geometrical properties.…”