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Interleukins 4 and 13 modulate gene expression and promote proliferation of primary human tenocytes
Courneya, Jean-Paul; Luzina, Irina G; Zeller, Cynthia B; Rasmussen, Jeffrey F; Bocharov, Alexander; Schon, Lew C; Atamas, Sergei P
BACKGROUND:Tendon disorders (tendinopathies) pose serious biomedical and socioeconomic problems. Despite diverse treatment approaches, the best treatment strategy remains unclear. Surgery remains the last resort because of the associated morbidity and inconsistent outcomes. We hypothesized that, similar to fibroblasts in various organs, tendon fibroblasts (tenocytes) might be responsive to stimulation with interleukins (ILs), particularly IL-4 and IL-13. These two cytokines share sequence homology, receptor chains and functional effects, including stimulation of fibrogenesis. It is unknown whether tenocytes are responsive to stimulation with IL-4 or IL-13. If true, local use of these cytokines might be used to facilitate tendon repair in patients with tendinopathies or used for tendon tissue-engineering approaches to facilitate tenocyte growth on scaffolds in culture. RESULTS:Tendon tissues that would normally be discarded were obtained during reconstructive surgery procedures performed for clinical indications. Primary tenocytes were derived from Achilles, posterior tibial, flexor digitorum longus and flexor hallucis longus tendon tissue samples. Reverse transcriptase quantitative PCR (RT-qPCR) experiments revealed that mRNAs for the receptor (R) chains IL-4Ralpha, IL-13Ralpha1 and IL-13Ralpha2, but not the common gamma-chain were present in all tested tendon tissues and in cultured tenocytes. Levels of IL-13R chain mRNAs were significantly higher than those of IL-4R mRNA. The cultures responded, in a dose-dependent fashion, to stimulation with recombinant human IL-4 or IL-13, by increasing proliferation rates 1.5 to 2.0-fold. The mRNA levels of 84 genes related to cell cycle regulation were measured by RT-qPCR after 6 h and 24 h of activation. The expression levels of several genes, notably CDK6 and CDKN2B changed more than twofold. In contrast to their effects on proliferation, stimulation with IL-4 or IL-13 had little if any effect on the levels of collagen mRNA or protein in cultured primary tenocytes. The mRNA levels of 84 other genes related to extracellular matrix and cell adhesion were also measured by RT-qPCR; expression of only five genes was consistently changed. CONCLUSIONS:Stimulation with IL-4 or IL-13 could be used to facilitate tendon repair in vivo or to aid in tendon tissue engineering, through stimulation of tenocyte proliferation.
PMCID:2893086
PMID: 20537133
ISSN: 1755-1536
CID: 3802502
Lateral Ankle Ligament Injuries in Athletes: Diagnosis and Treatment
Groth, Adam T.; Guyton, Gregory P.; Schon, Lew C.
Nonsurgical management is preferred in most ankle sprains, even in the athletic population. However, patients presenting with chronic lateral ankle instability refractory to an appropriate bracing and rehabilitation program may benefit from lateral ligament reconstruction. Recognition and management of other associated injuries or conditions is critical to a successful outcome. We present 2 surgical techniques for reconstruction of the lateral ankle ligaments in athletes. The periosteal flap augmentation of the modified Brostrom reconstruction should be considered for primary cases. Patients who have failed prior surgical reconstruction or have a systemic condition resulting in generalized ligamentous laxity may require further surgical augmentation with an anatomical allograft ligament reconstruction technique. Oper Tech Sports Med 18:18-26 (C) 2010 Elsevier Inc. All rights reserved. ISI:000276703600004
ISSN: 1060-1872
CID: 3803402
Assessment of the foot and ankle in elite athletes
Schon, Lew C
An accurate assessment of the foot and ankle problem in elite athletes is the foundation of a treatment plan and prognosis. The special pressures of professional sports, where managers, agents, and lawyers may be involved, makes a thorough assessment especially critical for sound decision-making. Evaluation includes taking a history of the acute and chronic condition, including mechanism, physical sensation at injury, compensatory stresses, and general medical review. The athlete is assessed physically in several different ways, including comprehensive focal examination and alignment in static and dynamic nonweight-bearing and weight-bearing modes. This comprehensive process is essential to accurate assessment.
PMID: 19440134
ISSN: 1538-1951
CID: 3802482
Melvin Jahss, MD (1921-2009) [Historical Article]
Schon, Lew C
PMID: 19356366
ISSN: 1071-1007
CID: 3802472
J.Leonard Goldner Award 2008. Effect of extracorporeal shock wave therapy on cultured tenocytes
Han, Seung Hwan; Lee, Jin Woo; Guyton, Gregory P; Parks, Brent G; Courneya, Jean-Paul; Schon, Lew C
BACKGROUND:Little has been reported about the biologic effect of shock waves on human normal or pathologic tendon tissue. We hypothesized that inflammatory cytokine and MMP production would be down-regulated by shock wave stimulation. MATERIALS AND METHODS/METHODS:Diseased Achilles tendon tissue and healthy flexor hallucis longus tissue were used. Shock wave treatment was applied to cultured cells at 0.17 mJ/mm(2)energy 250, 500, 1000, and 2000 times. RESULTS:A dose-dependent decrease in cell viability was noted in cells receiving 1000 and 2000 shocks (86.0 +/- 5.6%, p = 0.01 and 72.4 +/- 8.9%, p = 0.001) as compared with the normal control. Cell count in the 500-shock group increased by 23.4% as compared with the control (p = 0.05). The concentration of MMP 1, 2, and 13 was higher in diseased tenocytes as compared with normal cells (p = 0.04, all comparisons). IL-6 levels were higher in the diseased tenocytes as compared with normal tenocytes (44.10 +/- 16.72 versus 0.21 +/- 0.55 ng/ml, (p < 0.05). IL-1 levels in normal cells increased (2.24 +/- 5.02 ng/ml to 9.31 +/- 6.85 ng/ml) after shock wave treatment (p = 0.04). In diseased tenocytes, levels of MMP-1 (1.12 +/- 0.23 to 0.75 +/- 0.24 ng/ml; p = 0.04) and MMP-13 (1.43 +/- 0.11 to 0.80 +/- 0.15 ng/ml; p = 0.04) were significantly decreased after shock wave treatment. The IL-6 level in diseased tenocytes was decreased (44.10 +/- 16.72 to 14.66 +/- 9.49 ng/ml) after shock wave treatment (p = 0.04). CONCLUSION/CONCLUSIONS:Higher levels of MMPs and ILs were found in human tendinopathy-affected tenocytes as compared with normal cells. ESWT decreased the expression of several MMPs and ILs. CLINICAL RELEVANCE/CONCLUSIONS:This mechanism may play an important role in shock wave treatment of tendinopathy clinically.
PMID: 19254500
ISSN: 1071-1007
CID: 3802462
Effect of bupivacaine on cultured tenocytes
Scherb, Michael B; Han, Seung-Hwan; Courneya, Jean-Paul; Guyton, Gregory P; Schon, Lew C
Proliferation of cultured human fibroblasts and other types of cells has been shown to be hindered by exposure to local anesthetics, which are widely used in musculoskeletal medicine for their use in regional anesthesia, selective nerve blocks, bursography, and brisement. We hypothesized that bupivacaine would decrease cell proliferation and production of extracellular matrix components collagen and proteoglycan in healthy human tenocytes in culture. Primary human tenocyte cultures were prepared from samples of normal tendons obtained from healthy tissue that would otherwise have been discarded during lower extremity tendon transfer surgery. Samples were obtained from 6 patients, 5 women and 1 man with an average age of 69 years (range, 17-73 years). Five flexor digitorum longus tendon samples and 1 peroneus longus tendon sample were used. Harvested tendon tissues (5 mm(3)) were used as explants for primary cell cultures. To measure the proliferative response to bupivacaine, seeded cells were exposed to saline control or to various concentrations of bupivacaine in 1% fetal bovine serum DMEM/F12 or 10% fetal bovine serum DMEM/F12. The 1% fetal bovine serum medium demonstrated the pure bupivacaine effect, and 10% fetal bovine serum more closely approximated the in vivo environment. Seeded cells were starved of fetal bovine serum for 12 hours before exposure to phosphate-buffered saline (control group) and 500 microM bupivacaine (experimental group). This concentration of bupivacaine was selected because it was found to significantly hinder proliferation in both the 1% and 10% fetal bovine serum groups in our proliferation assay. Tenocyte proliferation and extracellular matrix component production were significantly lower (P<or=.05) at >or=1 time points up to 6 days in bupivacaine-treated groups as compared with controls.
PMID: 19226039
ISSN: 1938-2367
CID: 3802452
Accuracy of posterior subtalar joint injection without fluoroscopy
Kirk, Kevin L; Campbell, John T; Guyton, Gregory P; Schon, Lew C
Injection into the posterior subtalar joint has not been validated for accuracy using radiographic end points. We asked whether needle placement into a normal posterior subtalar joint could be performed accurately and selectively by experienced surgeons without fluoroscopic guidance. Three fellowship-trained orthopaedic foot and ankle surgeons each injected the posterior subtalar joint of 20 cadaveric specimens using an anterolateral approach. Fluoroscopic images were obtained by an independent investigator and blinded. A separate fellowship-trained foot and ankle surgeon interpreted the images. Of 60 injections, 58 were accurate and two were extraarticular based on interpretation by an independent foot and ankle surgeon. Extravasation into the ankle occurred in 14 samples and into the peroneal sheath in two samples. Experienced surgeons can place intraarticular injections into a radiographically normal posterior subtalar joint without fluoroscopy with a high degree of accuracy. However, extravasation into the ankle or peroneal tendon sheath occurred in an unpredictable fashion, suggesting selectivity of injection placement is relatively limited without the use of fluoroscopy. Fluoroscopy may not be necessary for injections used solely for therapeutic purposes. However, if the injection is intended for diagnostic purposes or to assist in surgical decision-making or if the joint is abnormal, we recommend fluoroscopy to ensure the subtalar joint is the only anatomic structure impacted by the injection.
PMCID:2565054
PMID: 18404293
ISSN: 1528-1132
CID: 3802392
ATFL elongation after Brostrom procedure: a biomechanical investigation
Kirk, Kevin L; Campbell, John T; Guyton, Gregory P; Parks, Brent G; Schon, Lew C
BACKGROUND:Elongation of ligaments during early mobilization after reconstruction may be associated with decreased stability. We evaluated elongation of the anterior talofibular ligament (ATFL) before and after lateral ligament reconstruction within a physiologic range of motion with protected and unprotected, isolated dorsiflexion/plantarflexion range of motion. MATERIALS AND METHODS/METHODS:Six fresh frozen cadaver legs were used with the ATFL meticulously dissected. A differential variable reluctance transducer (DVRT) was spaced to span the course of the ATFL using consistent placement points based on previous reports. Elongation was measured in a load frame with protected motion of 30 degrees plantarflexion and 10 degrees dorsiflexion for the intact and sectioned ATFL and for the repaired specimen with and without protected motion. The proximal DVRT anchor point was detached for sectioning and repair of the ATFL and replaced at the same position. Testing was 1000 cycles at 1 Hz for the repaired protected specimen and 10 cycles at 1 Hz for all other stages. RESULTS:Initial elongation in the unprotected, repaired group was significantly higher than initial elongation in the intact (p < 0.01), sectioned (p = 0.02), and repaired, protected (p < 0.01) groups. Final elongation in the unprotected repaired group was also higher than final elongation in all other groups (p < 0.01 for all comparisons). CONCLUSION/CONCLUSIONS:The use of protected range of motion of the ankle after lateral ankle ligament reconstruction was not associated with elongation of the ATFL. The ATFL elongated significantly by comparison without protected dorsiflexion/plantarflexion. CLINICAL RELEVANCE/CONCLUSIONS:The study provides biomechanical support for the safety of early protected dorsiflexion/plantarflexion range of motion after Broström reconstruction.
PMID: 19026207
ISSN: 1071-1007
CID: 3802442
Morton neuroma: primary and secondary neurectomy
Title, Craig I; Schon, Lew C
PMID: 18768712
ISSN: 1067-151x
CID: 3802412
Radiographic and pedobarographic comparison of femoral head allograft versus block plate with dorsal opening wedge medial cuneiform osteotomy: a biomechanical study
League, Alan C; Parks, Brent G; Schon, Lew C
BACKGROUND:The effect of the Cotton osteotomy has not been studied in isolation, and no alternative to bone graft has been investigated for this osteotomy. We hypothesized that there would be no difference in radiographic and pressure findings using the Cotton osteotomy with bone graft or an opening wedge block plate. MATERIALS AND METHODS/METHODS:Each specimen of eight matched pairs of lower extremities was loaded in simulated double-leg stance via pneumatic cylinders as described previously. Weightbearing lateral and anteroposterior radiographs and medial and lateral pressure measurements were obtained for all intact specimens. Specimens were randomly assigned to receive a Cotton osteotomy with a dorsal opening wedge allograft or an opening wedge plate. Each specimen was cycled at 3 Hz to 720 N for 5000 cycles and measurements were repeated. RESULTS:Calcaneal pitch was lower after the block plate procedure (mean +/- standard error of the mean) (intact, 23.4 +/- 1.2 degrees versus post-procedure, 21.8 +/- 1.1 degrees; p = 0.05). There was a significant difference (p < 0.05) in percentage of total plantar pressure medially and laterally between the intact specimen and the specimen after osteotomy with both methods. Pressure increased medially and decreased laterally. CONCLUSION/CONCLUSIONS:With the numbers available, these methods for performing a Cotton osteotomy did not differ in addressing lateral column overload. CLINICAL RELEVANCE/CONCLUSIONS:Dorsal opening wedge medial cuneiform osteotomy performed with femoral head allograft or a block plate may be effective both in reducing lateral column pressures and increasing medial column pressures when they are deficient preoperatively.
PMID: 18778672
ISSN: 1071-1007
CID: 3802422