From Meniscus to Bone: Structure and Function of Human Meniscal Entheses and Deleterious Effects of Osteoarthritis

Author

Adam Christopher Abraham

Abstract

Knee osteoarthritis plagues millions of people in the U.S. alone, yet the mechanisms of initialization are not well understood. Recent work suggests that there are a myriad of potential disease inducing routes that may give rise to this debilitating condition. Understanding and elucidating the potential pathways leading to osteoarthritis may result in novel methods of prevention and/or treatment. Human meniscus areC-shaped fibrocartilaginous structures contained within the diathroidal knee joint, the primary function of which are to provide support and lubrication between the femur and the tibia. Each knee incorporates two menisci, lateral and medial, affixed at the anterior and posterior attachment sites to the tibial plateau. Meniscal attachments, or entheses, are unique graded tissue interfaces comprised of four distinct zones that diffuse longitudinal loads transmitted via hoop stresses of collagen fibrils in the meniscal body. The attachments must remain firmly rooted to the tibial plateau to effectively attenuate joint loads. If the attachments become structurally compromised, either through direct or indirect means, excessive transverse meniscal translation results. Such joint extrusion of the meniscal body is a known precursor to developing osteoarthritis. To date there have been no investigations of integrity of meniscal attachments in the aged arthritic knee.

Link to Article

http://digitool.library.colostate.edu/exlibris/dtl/d3_1/apache_media/L2V4bGlicmlzL2R0bC9kM18xL2FwYWNoZV9tZWRpYS8yMDc0NjQ=.pdf

Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice

Authors

Sindhu K. Madathil, Shaun W. Carlson, Jennifer M. Brelsfoard, Ping Ye, A. Joseph D’Ercole, Kathryn E. Saatman

Abstract

Traumatic brain injury (TBI) survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1), a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal) overexpression of IGF-1 using the controlled cortical impact (CCI) injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited this regional astrocytosis by linking expression of hIGF-1 to the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, effectively targeting IGF-1 delivery to vulnerable neurons. Following brain injury, IGF-1Tg mice exhibited a progressive increase in hippocampal IGF-1 levels which was coupled with enhanced hippocampal reactive astrocytosis and significantly greater GFAP levels relative to WT mice. IGF-1 overexpression stimulated Akt phosphorylation and reduced acute (1 and 3d) hippocampal neurodegeneration, culminating in greater neuron survival at 10d after CCI injury. Hippocampal neuroprotection achieved by IGF-1 overexpression was accompanied by improved motor and cognitive function in brain-injured mice. These data provide strong support for the therapeutic efficacy of increased brain levels of IGF-1 in the setting of TBI.

Link to Article

http://dx.doi.org/10.1371/journal.pone.0067204

Effect of cell-seeded hydroxyapatite scaffolds on rabbit radius bone regeneration

Authors

C. R. Rathbone, T. Guda, B. M. Singleton, D. S. Oh, M. R. Appleford, J. L. Ong, J. C. Wenke

Abstract

Highly porous hydroxyapatite (HA) scaffolds were developed as bone graft substitutes using a template coating process, characterized, and seeded with bone marrow-derived mesenchymal stem cells (BMSCs). To test the hypothesis that cell-seeded HA scaffolds improve bone regeneration, HA scaffolds without cell seeding (HA-empty), HA scaffolds with 1.5 × 104 BMSCs (HA-low), and HA scaffolds with 1.5 × 106 BMSCs (HA-high) were implanted in a 10-mm rabbit radius segmental defect model for 4 and 8 weeks. Three different fluorochromes were administered at 2, 4, and 6 weeks after implantation to identify differences in temporal bone growth patterns. It was observed from fluorescence histomorphometry analyses that an increased rate of bone infiltration occurred from 0 to 2 weeks (p < 0.05) of implantation for the HA-high group (2.9 ± 0.5 mm) as compared with HA-empty (1.8 ± 0.8 mm) and HA-low (1.3 ± 0.2 mm) groups. No significant differences in bone formation within the scaffold or callus formation was observed between all groups after 4 weeks, with a significant increase in bone regenerated for all groups from 4 to 8 weeks (28.4% across groups). Although there was no difference in bone formation within scaffolds, callus formation was significantly higher in HA-empty scaffolds (100.9 ± 14.1 mm3) when compared with HA-low (57.8 ± 7.3 mm3; p ≤ 0.003) and HA-high (69.2 ± 10.4 mm3; p ≤ 0.02) after 8 weeks. These data highlight the need for a better understanding of the parameters critical to the success of cell-seeded HA scaffolds for bone regeneration.

Link to Article

http://dx.doi.org/10.1002/jbm.a.34834

Fracture healing with alendronate treatment in the Brtl/+ mouse model of osteogenesis imperfecta

Authors

J.A. Meganck, D.L. Begun, J.D. McElderry, A. Swick, K.M. Kozloff, S.A. Goldstein, M.D. Morris, J.C. Marini, M.S. Caird

Abstract

Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by increased skeletal fragility. Patients are often treated with bisphosphonates to attempt to reduce fracture risk. However, bisphosphonates reside in the skeleton for many years and long-term administration may impact bone material quality. Acutely, there is concern about risk of non-union of fractures that occur near the time of bisphosphonate administration. This study investigated the effect of alendronate, a potent aminobisphosphonate, on fracture healing. Using the Brtl/+ murine model of type IV OI, tibial fractures were generated in 8-week-old mice that were untreated, treated with alendronate before fracture, or treated before and after fracture. After 2, 3, or 5 weeks of healing, tibiae were assessed using microcomputed tomography (μCT), torsion testing, quantitative histomorphometry, and Raman microspectroscopy. There were no morphologic, biomechanical or histomorphometric differences in callus between untreated mice and mice that received alendronate before fracture. Alendronate treatment before fracture did not cause a significant increase in cartilage retention in fracture callus. Both Brtl/+ and WT mice that received alendronate before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5 weeks of healing. Raman microspectroscopy results did not show any effects of alendronate in wild-type mice, but calluses from Brtl/+ mice treated with alendronate during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with alendronate altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture.

Link to Article

http://dx.doi.org/10.1016/j.bone.2013.06.003

Immunohistochemical characterization of axonal sprouting in mice

Authors

Erin J. Feeney, Diane Stephenson, Robin Kleiman, Susan Bove, Courtney Cron, Lara Moody, Mercedes Robinson, Julio J. Ramirez

Abstract

Purpose: Transgenic manipulation of mouse physiology facilitates the preclinical study of genetic risk factors, neural plasticity, and reactive processes accompanying Alzheimer's disease. Alternatively, entorhinal cortex lesions (ECLs) model pathophysiological denervation and axonal sprouting in rat. Given reports of anatomical differences between the mouse and rat hippocampus, application of the ECL paradigm to transgenic mice first requires comprehensive characterization of axonal sprouting in the wild-type. Methods: Adult male C57BL/6 mice sustained unilateral transections of the perforant pathway. Subjects were sacrificed at 1, 4, 10, 18, and 28 days postlesion, and hippocampal sections were stained for AChE, the postsynaptic terminal marker drebrin, and the presynaptic terminal proteins SNAP-25, GAP-43, synapsin, and synaptophysin. To examine synaptic turnover and reinnervation, ipsilateral-to-contralateral staining densities were determined within the dentate molecular layer, and shrinkage-corrected ratios were compared to 28 day-yoked sham cases. Results: At 28 days postlesion, ipsilateral terminal marker densities exhibited significant depression. In contrast, qualitative analyses at earlier time points suggested altered AChE staining patterns and increased SNAP-25 and synapsin immunoreactivity in the inner molecular layer (IML) of the dentate gyrus. Conclusions: C57BL/6 mice exhibit synaptic reorganization following perforant path transections. The IML may provide a key target for evaluation and intervention in ECL mouse models.

Link to Article

http://dx.doi.org/10.3233/RNN-130311

Porous Tantalum Coatings Prepared by Vacuum Plasma Spraying Enhance BMSCs Osteogenic Differentiation and Bone Regeneration In Vitro and In Vivo

Authors

Ze Tang, Youtao Xie, Fei Yang, Yan Huang, Chuandong Wang, Kerong Dai, Xuebin Zheng, Xiaoling Zhang

Abstract

Tantalum, as a potential metallic implant biomaterial, is attracting more and more attention because of its excellent anticorrosion and biocompatibility. However, its significantly high elastic modulus and large mechanical incompatibility with bone tissue make it unsuitable for load-bearing implants. In this study, porous tantalum coatings were first successfully fabricated on titanium substrates by vacuum plasma spraying (VPS), which would exert the excellent biocompatibility of tantalum and alleviate the elastic modulus of tantalum for bone tissue. We evaluated cytocompatibility and osteogenesis activity of the porous tantalum coatings using human bone marrow stromal cells (hBMSCs) and its ability to repair rabbit femur bone defects. The morphology and actin cytoskeletons of hBMSCs were observed via electron microscopy and confocal, and the cell viability, proliferation and osteogenic differentiation potential of hBMSCs were examined quantitatively by PrestoBlue assay, Ki67 immunofluorescence assay, real-time PCR technology and ALP staining. For in vivo detection, the repaired femur were evaluated by histomorphology and double fluorescence labeling 3 months postoperation. Porous tantalum coating surfaces promoted hBMSCs adhesion, proliferation, osteogenesis activity and had better osseointegration and faster new bone formation rate than titanium coating control. Our observation suggested that the porous tantalum coatings had good biocompatibility and could enhance osseoinductivity in vitro and promote new bone formation in vivo. The porous tantalum coatings prepared by VPS is a promising strategy for bone regeneration.

Link to Article

http://dx.doi.org/10.1371/journal.pone.0066263