Abstract
Growth hormone (GH) deficiency and loss of physical activity are common features in traumatic brain injury (TBI) patients that may contribute to bone loss. Therefore, we tested the hypothesis that GH treatment will rescue the hind limb unloading (UL)-induced skeletal deficit in TBI mice. Mild TBI was induced once per day for four consecutive days. UL (right hind limb) and treatment (3 mg/day GH or vehicle) began two weeks after the first TBI episode and lasted for four weeks. GH treatment increased femur BMD and lean body mass but decreased the % fat measured by DXA in the Control group. Micro-CT analysis revealed that the TBI, UL and TBI-UL groups showed reduced tibia trabecular (Tb) bone mass by 15%, 70%, and 75%, respectively compared to Control mice and that GH treatment significantly increased Tb. bone mass in all four groups. Vertebra also showed reduced Tb. bone mass in TBI, UL and TBI-UL groups. GH treatment increased vertebral Tb. bone mass in Control and UL groups but not in the TBI or TBI-UL group. GH treatment increased serum IGF-I levels similarly in TBI, UL and TBI-UL groups at day 14, suggesting the GH effect on liver IGF-I production was unaffected by skeletal UL. In contrast, GH effect on expression of ALP, IGFBP5 and axin2 in bone were compromised by UL. In conclusion, skeletal UL caused a greater Tb. bone deficit than mild TBI alone and that GH anabolic effects in the TBI and UL groups vary depending on the skeletal site.
Highlights
The hypothalamus transmits signals from the brain to the pituitary gland by stimulating endocrine factors that are essential for maintaining homeostasis and regulating skeletal integrity[6]
We recently demonstrated that repeated mild traumatic brain injury (TBI) to the brain exerts a significant negative effect on bone mass accretion in mice that is caused in part due to alterations of the Growth hormone (GH)/IGF-1 axis[16]
Based on the findings that TBI leads to dysregulation of the GH/IGF-1 axis and that unloading induces skeletal resistance to IGF-1 effects, we tested if the negative effects of TBI on bone mass are exaggerated by skeletal unloading, and if the negative effects of TBI and unloading on bone mass can be rescued by replacement GH therapy
Summary
The hypothalamus transmits signals from the brain to the pituitary gland by stimulating endocrine factors that are essential for maintaining homeostasis and regulating skeletal integrity[6]. Many studies have reported hypothalamus-pituitary dysfunction post TBI, with both adverse acute and long-term effects in patients[7,8,9,10]. In TBI, the hypothalamus-pituitary function is disrupted, leading to multiple hormone deficiencies, in growth hormone (GH) production. Several studies have reported GH deficiency in 14–21% of TBI patients[7,11]. We have previously shown that two weeks of GH treatment significantly increased total body bone mineral density (BMD) by as much as 15% in GH deficient lit/lit mice[12]. GH deficiency is a common adverse effect in TBI patients that may contribute to bone loss. We recently demonstrated that repeated mild TBI to the brain exerts a significant negative effect on bone mass accretion in mice that is caused in part due to alterations of the GH/IGF-1 axis[16]. Based on the findings that TBI leads to dysregulation of the GH/IGF-1 axis and that unloading induces skeletal resistance to IGF-1 effects, we tested if the negative effects of TBI on bone mass are exaggerated by skeletal unloading, and if the negative effects of TBI and unloading on bone mass can be rescued by replacement GH therapy
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