The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury

AUTHORS

Floriane Bretheau, Adrian Castellanos-Molina, Benoit Mailhot, Maxime Kusik, Dominic Belanger, Martine Lessard, Nicolas Vallières, Xiaoyu Liu, Ning Quan, Steve Lacroix

ABSTRACT

Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)-1α is released by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induced neutrophil infiltration and OL death throughout the spinal cord, mimicking what is seen at sites of SCI. These effects were abolished by co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which showed enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restored IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduced OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes is toxic for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS) and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, which induces astrocyte- and EC-mediated OL degeneration.

A comprehensive study of long-term skeletal changes after spinal cord injury in adult rats

Authors

Tiao Lin, Wei Tong, Abhishek Chandra, Shao-Yun Hsu, Haoruo Jia, Ji Zhu, Wei-Ju Tseng, Michael A Levine, Yejia Zhang, Shi-Gui Yan, X Sherry Liu, Dongming Sun, Wise Young & Ling Qin

Abstract

Spinal cord injury (SCI)-induced bone loss represents the most severe osteoporosis with no effective treatment. Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To mimic chronic SCI in human patients, we performed a comprehensive analysis of long-term structural and mechanical changes in axial and appendicular bones in adult rats after SCI. In this experiment, 4-month-old Fischer 344 male rats received a clinically relevant T13 contusion injury. Sixteen weeks later, sublesional femurs, tibiae, and L4 vertebrae, supralesional humeri, and blood were collected from these rats and additional non-surgery rats for micro-computed tomography (µCT), micro-finite element, histology, and serum biochemical analyses. At trabecular sites, extreme losses of bone structure and mechanical competence were detected in the metaphysis of sublesional long bones after SCI, while the subchondral part of the same bones showed much milder damage. Marked reductions in bone mass and strength were also observed in sublesional L4 vertebrae but not in supralesional humeri. At cortical sites, SCI induced structural and strength damage in both sub- and supralesional long bones. These changes were accompanied by diminished osteoblast number and activity and increased osteoclast number and activity. Taken together, our study revealed site-specific effects of SCI on bone and demonstrated sustained inhibition of bone formation and elevation of bone resorption at the chronic stage of SCI.

Link to Article

http://dx.doi.org/10.1038%2Fboneres.2015.28

Treatment with curcumin alleviates sublesional bone loss following spinal cord injury in rats

Authors

Xiaobin Yang, Baorong He, Peng Liu, Liang Yan, Ming Yang, Dichen Li

Abstract

This work aimed to investigate the therapeutic effect of curcumin on sublesional bone loss induced by spinal cord injury (SCI) in rats. SCI model in this work was generated in rats by surgical transaction of the cord at the T10–12 level. After the surgery, animals were treated with curcumin (110 mg/kg body mass/day, via oral gavages) for 2 weeks. Treatment of SCI rats with curcumin prevented the reduction of bone mass in tibiae and femurs, preserved bone microstructure including trabecular bone volume fraction, trabecular number, and trabecular thickness in proximal tibiae, and preserved mechanical properties of femoral midshaft. Treatment of SCI rats with curcumin increased osteoblast surface and reduced osteoclast surface in proximal tibiae. Treatment of SCI rats with curcumin increased osteocalcin mRNA expression and reduced mRNA levels of tartrate-resistant acid phosphatase and mRNA ratio of receptor activator of NF-κB ligand/osteoprotegerin in distal femurs. Treatment of SCI rats with curcumin reduced serum and femoral levels of thiobarbituric acid reactive substances. Treatment of SCI rats with curcumin had no significant effect on serum 25(OH)D, but enhanced mRNA and protein expression of vitamin D receptor (VDR) in distal femurs. Treatment of SCI rats with curcumin enhanced mRNA levels of Wnt3a, Lrp5, and ctnnb1 and upregulated protein expression of β-catenin in distal femurs. In conclusions, treatment with curcumin abated oxidative stress, activated VDR, and enhanced Wnt/β-catenin pathway, which might explain its beneficial effect against sublesional bone loss following SCI in rats, at least in part.

Link to Article

http://dx.doi.org/10.1016/j.ejphar.2015.08.036

Maximizing bone formation in posterior spine fusion using rhBMP-2 and zoledronic acid in wild type and NF1 deficient mice

Authors

Justin Bobyn, Anton Rasch, Mikulec Kathy, David G. Little, and Aaron Schindeler

Abstract

Spinal pseudarthrosis is a well described complication of spine fusion surgery in NF1 patients. Reduced bone formation and excessive resorption have been described in NF1 and anti-resorptive agents may be advantageous in these individuals. In this study, 16 wild type and 16 Nf1+/− mice were subjected to posterolateral fusion using collagen sponges containing 5 µg rhBMP-2 introduced bilaterally. Mice were dosed twice weekly with 0.02 mg/kg zoledronic acid (ZA) or sterile saline. The fusion mass was assessed for bone volume (BV) and bone mineral density (BMD) by microCT. Co-treatment using rhBMP-2 and ZA produced a significant increase (p < 0.01) in BV of the fusion mass compared to rhBMP-2 alone in both wild type mice (+229%) and Nf1+/− mice (+174%). Co-treatment also produced a significantly higher total BMD of the fusion mass compared to rhBMP-2 alone in both groups (p < 0.01). Despite these gains with anti-resorptive treatment, Nf1+/− deficient mice still generated less bone than wild type controls. TRAP staining on histological sections indicated an increased osteoclast surface/bone surface (Oc.S/BS) in Nf1+/− mice relative to wild type mice, and this was reduced with ZA treatment.

Link To Article

http://dx.doi.org/10.1002/jor.22628