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OBJECTIVE - Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA.
METHODS - OA severity was histologically assessed in 4-month-old wild-type and REDD1 mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild-type and REDD1 mice.
RESULTS - REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1 mice and in cultured REDD1 mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule-associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1 mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1-deficient chondrocytes. REDD1 was required for AMP-activated protein kinase-induced PGC-1α in chondrocytes.
CONCLUSION - Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury-induced OA.
© 2017, American College of Rheumatology.
The risk of developing post-traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help to improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA; however, the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild-type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following (1)H nuclear magnetic resonance spectroscopy, we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice and the integrin α1-null versus wild-type mouse genotype. Our results show the sex-dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA, and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site-specific factors such as surgery.
BACKGROUND - Anomalies of the meniscus are uncommon. These anomalous formations have been predominately described in the lateral compartment of the knee. Congenital abnormalities of the medial meniscus are rare.
METHODS - Chart and radiographic review of a single patient with a symptomatic congenital abnormality of the medial meniscus.
RESULTS - The patient was a 5-year-old boy with popliteal pterygium who developed painful snapping in the medial knee after anterior hemiepiphyseodesis to improve his knee extension. The patient had achieved full-knee extension from a preoperative 45-degree flexion contracture. The newly developed snapping was attributed to the hemiepiphyseodesis implants. After implant removal, the snapping persisted and was localized at the medial joint line. Through an arthrotomy, a medial meniscus abnormality was identified and excised with resolution of symptoms.
CONCLUSIONS - This report describes a symptomatic congenital abnormality of the medial meniscus in a child with popliteal pterygium. The patient was treated with excision of the anomalous structure with complete resolution of the symptoms. This is the first report of an intra-articular knee anomaly associated with popliteal pterygium syndrome.
BACKGROUND - Meniscal repair is performed in an attempt to prevent posttraumatic arthritis resulting from meniscal dysfunction after meniscal tears. The socioeconomic implications of premature arthritis are significant in the young patient population. Investigations and techniques focusing on meniscus preservation and healing are now at the forefront of orthopaedic sports medicine.
HYPOTHESIS - Concomitant meniscal repair with anterior cruciate ligament reconstruction is a durable and successful procedure at 2-year follow-up.
STUDY DESIGN - Case series; Level of evidence, 4.
METHODS - All unilateral primary anterior cruciate ligament reconstructions entered in 2002 in a cohort who had meniscal repair at the time of anterior cruciate ligament reconstruction were evaluated. Validated patient-oriented outcome instruments were completed preoperatively and then again at the 2-year postoperative time point. Reoperation after the index procedure was also documented and confirmed by operative reports.
RESULTS - A total of 437 unilateral primary anterior cruciate ligament reconstructions were performed with 82 concomitant meniscal repairs (54 medial, 28 lateral) in 80 patients during the study period. Patient follow-up was obtained on 94% (77 of 82) of the meniscal repairs, allowing confirmation of meniscal repair success (defined as no repeat arthroscopic procedure) or failure. The overall success rate for meniscal repairs was 96% (74 of 77 patients) at 2-year follow-up.
CONCLUSION - Meniscal repair is a successful procedure in conjunction with anterior cruciate ligament reconstruction. When confronted with a "repairable" meniscal tear at the time of anterior cruciate ligament reconstruction, orthopaedic surgeons can expect an estimated >90% clinical success rate at 2-year follow-up using a variety of methods as shown in our study.
Since meniscal healing is region-specific, we studied the regional (peripheral compared with central) response of meniscal explants to human, recombinant platelet-derived growth factor-AB. Meniscal explants from the hindlimbs of both knees of mature sheep were sectioned and were cultured with variable doses of human, recombinant platelet-derived growth factor-AB, and incorporation of [3H]-thymidine was measured. The mitogenic response was measured at different times in culture (48 or 96 hours) and by location (lateral or medial). In the absence of the growth factor, the peripheral third of both menisci incorporated 10-fold more [3H]-thymidine on a weight basis than did the central two-thirds. Cellularity was equivalent in the two regions. Doses of less than 100 ng/ml of growth factor produced either no stimulation or a variable response. A dose of 100 ng/ml resulted in consistent, significant (p < 0.05) stimulation in all groups in the peripheral region, and a dose of 200 ng/ml provided more than a 2.5-fold increase. Multiple-factor analysis of variance demonstrated that there were no significant differences between experiments, times in culture, or menisci. The central region did not respond to stimulation with the growth factor at any of the doses tested. These data suggest that regional differences (peripheral compared with central) in responsiveness to human, recombinant platelet-derived growth factor-AB may reflect a different level of signal transduction machinery for growth factor receptors and distinct fibrobchondrocyte populations. These findings are consistent with the variable healing capacity of the meniscal regions in vivo and suggest a pharmacological means to promote the repair of the peripheral meniscal region.