The new hernia model appears to be very useful for studying herniated disc resorption. Intervertebral disc cells may produce inflammatory cytokines/chemokine immediately after the onset of disc herniation, possibly triggering subsequent macrophage infiltration that leads to disc resorption.

No abstract

We have investigated in vitro the release kinetics and bioactivity of fibroblast growth factor-2 (FGF-2) released from a carrier of fibrin sealant. In order to evaluate the effects of the FGF-2 delivery mechanism on the repair of articular cartilage, full-thickness cylindrical defects, 5 mm in diameter and 4 mm in depth, which were too large to undergo spontaneous repair, were created in the femoral trochlea of rabbit knees. These defects were then filled with the sealant. Approximately 50% of the FGF-2 was released from the sealant within 24 hours while its original bioactivity was maintained. The implantation of the fibrin sealant incorporating FGF-2 successfully induced healing of the surface with hyaline cartilage and concomitant repair of the subchondral bone at eight weeks after the creation of the defect. Our findings suggest that this delivery method for FGF-2 may be useful for promoting regenerative repair of full-thickness defects of articular cartilage in humans.

Chronic inflammation and subsequent fibrosis induced by mechanical stress play an important role in ligamentum flavum (LF) hypertrophy and degeneration in patients with lumbar spinal canal stenosis (LSCS). Angiopoietin-like protein 2 (Angptl2) is a chronic inflammatory mediator induced under various pathological conditions and increases the expression of TGF-β1, which is a well-characterized mediator in LF hypertrophy. We investigated whether Angptl2 is induced by mechanical stress, and whether it contributes to LF hypertrophy and degeneration by activating the TGF-β1 signaling cascade. In this study, we investigated human LF tissue and LF fibroblasts isolated from patients who underwent lumbar surgery. We found that Angptl2 was abundantly expressed in fibroblasts of hypertrophied LF tissues at both the mRNA and protein levels. This expression was not only positively correlated with LF thickness and degeneration but also positively correlated with lumbar segmental motion. Our in vitro experiments with fibroblasts from hypertrophied LF tissue revealed that mechanical stretching stress increases the expression and secretion of Angptl2 via activation of calcineurin/NFAT pathways. In hypertrophied LF tissue, expression of TGF-β1 mRNA was also increased and TGF-β1/Smad signaling was activated. Angptl2 expression in LF tissue was positively correlated with the expression of TGF-β1 mRNA, suggesting cooperation between Angptl2 and TGF-β1 in the pathogenesis of LF hypertrophy. In vitro experiments revealed that Angptl2 increased levels of TGF-β1 and its receptors, and also activated TGF-β1/Smad signaling. Mechanical stretching stress increased TGF-β1 mRNA expression, which was partially attenuated by treatment with a calcineurin/NFAT inhibitor or Angptl2 siRNA, indicating that induction of TGF-β1 expression by mechanical stretching stress is partially mediated by Angptl2. We conclude that expression of Angptl2 induced by mechanical stress in LF fibroblasts promotes LF tissue degeneration by activation of TGF-β1/Smad signaling, which results in LF hypertrophy in patients with LSCS.

In this study we investigated the cellular events that occur during the onset of chondrogenic differentiation during the repair of full-thickness defects of articular cartilage. The V-shaped full-thickness cartilage defects (width 0.7 or 1.5 mm; depth 0.8 mm; length 4 mm) were created in the femoral patellar groove of rats using a custom-built twin-blade device. The time course of the repair response in these cartilage defects was examined using a semi-quantitative histological grading scale. Cartilaginous repair responses failed to occur in the larger 1.5 mm defects, which was covered only by fibrous scar tissue. In contrast, hyaline-like articular cartilage was regenerated concomitantly with the repair of the subchondral bone by 4 weeks in smaller 0.7 mm width defects. Cells in the reparative regions were then characterized by immunohistochemistry and in situ hybridization. Undifferentiated mesenchymal cells migrate into the defects and fill the cavities within 4 days of their creation. The expression of PCNA, N-cadherin, and PTH/PTHrP receptors was induced in cells at the center of the defects, where type II collagen-positive polygonal-shaped cells also begin to appear at day 7. Marrow-derived mesenchymal cells acquire higher levels of proliferative activity in induced cartilage cavities after their initial migration and filling of the smaller 0.7 mm defects. During the regenerative repair of articular cartilage in the rat, there is a distinctive step that appears to be analogous to the precartilaginous condensation that is pivotal during chondrogenesis in development.