Lars G. Gilbertson

Biomechanical consequences of a tear of the posterior root of the medial meniscus: Similar to total meniscectomy

BACKGROUND Tears of the posterior root of the medial meniscus are becoming increasingly recognized. They can cause rapidly progressive arthritis, yet their biomechanical effects are not understood. The goal of this study was to determine the effects of posterior root tears of the medial meniscus and their repairs on tibiofemoral joint contact pressure and kinematics. METHODS Nine fresh-frozen cadaver knees were used. An axial load of 1000 N was applied with a custom testing jig at each of four knee-flexion angles: 0 degrees, 30 degrees, 60 degrees, and 90 degrees. The knees were otherwise unconstrained. Four conditions were tested: (1) intact, (2) a posterior root tear of the medial meniscus, (3) a repaired posterior root tear, and (4) a total medial meniscectomy. Fuji pressure-sensitive film was used to record the contact pressure and area for each testing condition. Kinematic data were obtained by using a robotic arm to record the position of the knees for each loading condition. Three-dimensional knee kinematics were analyzed with custom programs with use of previously described transformations. The measured variables were axial rotation, varus angulation, lateral translation, and anterior translation. RESULTS In the medial compartment, a posterior root tear of the medial meniscus caused a 25% increase in peak contact pressure compared with that found in the intact condition (p < 0.001). Repair restored the peak contact pressure to normal. No difference was detected between the peak contact pressure after the total medial meniscectomy and that associated with the root tear. The peak contact pressure in the lateral compartment after the total medial meniscectomy was up to 13% greater than that for all other conditions (p = 0.026). Significant increases in external rotation and lateral tibial translation, compared with the values in the intact knee, were observed in association with the posterior root tear (2.98 degrees and 0.84 mm, respectively) and the meniscectomy (4.45 degrees and 0.80 mm, respectively), and these increases were corrected by the repair. CONCLUSIONS This study demonstrated significant changes in contact pressure and knee joint kinematics due to a posterior root tear of the medial meniscus. Root repair was successful in restoring joint biomechanics to within normal conditions.

Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation

Recent studies have shown that mesenchymal stem cell (MSC)‐based therapy might be an effective approach for the treatment of intervertebral disc degeneration (IDD). However, many unanswered questions remain before clinical translation, such as the most effective stem cell type, a reliable transplantation method, including the carrier choice, and the fate of stem cells after misdirected delivery, among others. The objective of the study was to evaluate the fate and effect of allogenic bone marrow MSCs after transplantation into an IDD model. The L2–3, L3–4 and L4–5 intervertebral discs (IVDs) of four rabbits were stabbed to create IDD. Rabbit MSCs were expanded in vitro and in part transduced with retrovirus/eGFP. After 3 weeks, 1 × 105 MSCs were injected into the IVDs. The rabbits were followed by X‐ray and MRI 3 and 9 weeks after injection. Then the animals were sacrificed and the spines analysed histologically. MRI showed no signs of regeneration. X‐ray and gross anatomy inspection demonstrated large anterolateral osteophytes. Histological analysis showed that the osteophytes were composed of mineralized tissue surrounded by chondrocytes, with the labelled MSCs among the osteophyte‐forming cells. The labelled MSCs were not found in the nucleus. Inflammatory cells were not observed in any injected IVDs. These results raise concern that MSCs can migrate out of the nucleus and undesirable bone formation may occur. While cause cannot be inferred from this study, the presence of MSCs in the osteophytes suggests a potential side‐effect with this approach. IVD regeneration strategies need to focus on cell carrier systems and annulus‐sealing technologies to avoid pitfalls. Copyright

p38 MAPK Inhibition Modulates Rabbit Nucleus Pulposus Cell Response to IL-1

Analysis of disc gene expression implicated IL‐1 in the development of intervertebral disc degeneration (IDD) in a rabbit stab model. The purpose of these studies is to determine the role of p38 Mitogen Activated Protein Kinase (p38 MAPK) signaling in nucleus pulposus cell response to IL‐1, and to compare rabbit nucleus pulposus (rNP) cell responses to IL‐1 activation with those in a stab model of disc degeneration. NP cells maintained in alginate bead culture were exposed to IL‐1, with or without p38 MAPK inhibition. RNA was isolated for reverse transcription polymerase chain reaction (RT‐PCR) analysis of gene expression, conditioned media analyzed for accumulation of nitric oxide (NO) and prostaglandin E‐2 (PGE‐2), and proteoglycan synthesis measured after 10 days. IL‐1 upregulation of mRNA for cycloxygenase‐2 (COX‐2), matrix metalloproteinase‐3 (MMP‐3), IL‐1, and IL‐6, was blunted by p38 inhibition while downregulation of matrix proteins (collagen I, collagen II, aggrecan) and insulin‐like‐growth‐factor I (IFG‐1) was also reversed. mRNA for tissue inhibitor of matrixmetalloproteinase‐1 (TIMP‐1) was modestly increased by IL‐1, while those for Transforming Growth Factor‐β (TGF‐β) SOX‐9, and versican remained unchanged. Blocking p38 MAPK reduced IL‐1 induced NO and PGE‐2 accumulation and partially restored proteoglycan synthesis. p38 MAPK inhibition in control cells increased mRNA for matrix proteins (aggrecan, collagen II, versican, collagen I) and anabolic factors (IGF‐1, TGF, and SOX‐9) from 50% to 120%, decreased basal PGE‐2 accumulation, but had no effect on message for TIMP‐1, MMP‐3, or COX‐2. Inhibition of p38 MAPK in cytokine‐activated disc cells blunts gene expression and production of factors associated with inflammation, pain, and disc matrix catabolism while reversing IL‐1 downregulation of matrix protein gene expression and proteoglycan synthesis. The results support the hypothesis that IL‐1 could be responsible for many of the mRNA changes seen in rabbit NP in the stab model of disc degeneration, and uphold the concept that development of molecular techniques to block p38 MAPK could provide a therapeutic approach to slow the course of intervertebral disc degeneration.