Excessive Growth Hormone Expression in Male GH Transgenic Mice Adversely Alters Bone Architecture and Mechanical Strength

Abstract

Patients with acromegaly have a higher prevalence of vertebral fractures despite normal bone mineral density (BMD), suggesting that GH overexpression has adverse effects on skeletal architecture and strength. We used giant bovine GH (bGH) transgenic mice to analyze the effects of high serum GH levels on BMD, architecture, and mechanical strength. Five-month-old hemizygous male bGH mice were compared with age- and sex-matched nontransgenic littermates controls (NT; n=16/group). Bone architecture and BMD were analyzed in tibia and lumbar vertebrae using microcomputed tomography. Femora were tested to failure using three-point bending and bone cellular activity determined by bone histomorphometry. bGH transgenic mice displayed significant increases in body weight and bone lengths. bGH tibia showed decreases in trabecular bone volume fraction, thickness, and number compared with NT ones, whereas trabecular pattern factor and structure model index were significantly increased, indicating deterioration in bone structure. Although cortical tissue perimeter was increased in transgenic mice, cortical thickness was reduced. bGH mice showed similar trabecular BMD but reduced trabecular thickness in lumbar vertebra relative to controls. Cortical BMD and thickness were significantly reduced in bGH lumbar vertebra. Mechanical testing of femora confirmed that bGH femora have decreased intrinsic mechanical properties compared with NT ones. Bone turnover is increased in favor of bone resorption in bGH tibia and vertebra compared with controls, and serum PTH levels is also enhanced in bGH mice. These data collectively suggest that high serum GH levels negatively affect bone architecture and quality at multiple skeletal sites.

Reduction of trabecular and cortical volumetric bone mineral density at the proximal femur in patients with acromegaly

“…However, future studies using finite element analysis of the QCT images are needed in order to clarify if the pattern described in our report is associated with altered strength and resistance across the proximal femur in patients exposed to GH/IGF1 excess. Of note, overexpression of GH in mice is associated with accelerated bone turnover and low cortical vBMD of the vertebrae, femur, and tibia leading to deterioration of bone mechanical strength (27). Mazziotti et al (15) demonstrated that aBMD at the FN decreased in both active and controlled ACRO patients during a 3-year follow-up and this reduction significantly predicted vertebral fractures in controlled ACRO.…”

Regulation of bone mineral density in the grey squirrel, Sciurus carolinensis: Bioavailability of calcium oxalate, and implications for bark stripping

“…There was no difference in femoral length or width, so this likely indicates the cortical tissue perimeter has thinned, as has been shown in mice (Lim et al., 2015). This means less cortical bone was present in the femurs of squirrels on the CaOx than those on the control diet.…”

Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: Lessons from mouse models

“…Indeed, several models of overexpression of GHRH (6, 7), the human (h) (8–14) or bovine (b) GH in mice have demonstrated increased body size and skeletal gigantism (10, 15–21). In this review we will focus on the skeletal phenotype of models overexpressing bGH, which activates the endogenous mouse GHR, as opposed to the hGH transgene, which activates both the GHR and the prolactin receptor.…”

“…All studies of transgenic mice with excess endogenous or transgenic bGH reported increases in bone size (length and diameter) and overall increases in bone mineral density (BMD). However, detailed analyses of skeletal properties revealed that systemic GH overexpression resulted in sex-specific and age-specific effects on the skeleton and impaired bone architecture and mechanical properties (15, 17, 19, 21). Overexpression of the hGHRH (20) resulted in systemic stimulation of endogenous GH and IGF-1 leading to initial increase in bone mass.…”

“…Studies with mice overexpressing the bGH under the global metallothionein (MMT-1) promoter (MMT-1-bGH mice) have shown increases in cortical bone cross-sectional area with thinner cortexes, effects that were more profound in male mice (17, 19, 21). With respect to the trabecular bone compartment most studies showed increases in trabecular bone volume predominantly in females (17, 19, 21), while a recent study indicates reductions in trabecular bone in male mice (15). With respect to increased/excess GH activity we should note that the SOCS2 null mice, which exhibit aberrant GH signaling due to lack of feedback inhibition, are larger than controls despite normal levels of circulating IGF-1 (22).…”