Objectives Osteoarthritis (OA) is associated with cell death and extracellular matrix degradation in articular cartilage. Autophagy is an essential cellular homeostasis mechanism that was found to be deficient in aging and OA cartilage. This study determined whether pharmacological inhibition of the mammalian target of rapamycin (mTOR), a key inhibitor of autophagy, has disease-modifying activity in experimental OA. Methods Experimental OA was induced by transection of the medial meniscotibial ligament and the medial collateral ligament in 2-month old C57Bl/6 mice (n=36). Rapamycin (1 mg/kg weight/day) (n=18 mice) or DMSO vehicle control (n=18 mice) was administered intraperitoneally for 10 weeks. Histopathological changes in articular cartilage and synovium were examined by using semiquantitative scoring systems. Rapamycin effects on mTOR signaling, autophagy, cartilage homeostasis and inflammation were analyzed by immunohistochemistry and immunofluorescence staining. Results Rapamycin affected the mTOR signaling pathway in mouse knee joints as indicated by inhibition of ribosomal protein S6 phosphorylation, a target of mTOR and activation of LC3, a main marker of autophagy. The severity of cartilage degradation was significantly (P < 0.01) reduced in the rapamycin treated group compared to the control group and this was associated with a significant (P < 0.05) decrease in synovitis. Rapamycin treatment also maintained cartilage cellularity, and decreased ADAMTS-5 and IL-1β expression in articular cartilage. Conclusions These results suggest that rapamycin, at least in part by autophagy activation, reduces the severity of experimental OA. Pharmacological activation of autophagy may be an effective therapeutic approach for OA.

Objective Meniscus lesions following trauma or associated with osteoarthritis (OA) have been described, yet meniscus aging has not been systematically analyzed. The objectives of this study were to (i) establish standardized protocols for representative macroscopic and microscopic analysis, (ii) improve existing scoring systems, and (iii) apply these techniques to a large number of human menisci. Design Medial and lateral menisci from 107 human knees were obtained and cut in two different planes (triangle/crossection and transverse/horizontal) in three separate locations (mid portion, anterior and posterior horns). All sections included vascular and avascular regions and were graded for i) surface integrity, ii) cellularity, iii) matrix/fiber organization and collagen alignment, and iv) Safranin-O staining intensity. The cartilage in all knee compartments was also scored. Results The new macroscopic and microscopic grading systems showed high inter-reader and intra-reader intraclass correlation coefficients. The major age-related changes in menisci in joints with no or minimal OA included increased Safranin-O staining intensity, decreased cell density, the appearance of acellular zones, and evidence of mucoid degeneration with some loss of collagen fiber organization. The earliest meniscus changes occurred predominantly along the inner rim. Menisci from OA joints showed severe fibrocartilaginous separation of the matrix, extensive fraying, tears and calcification. Abnormal cell arrangements included decreased cellularity, diffuse hypercellularity along with cellular hypertrophy and abnormal cell clusters. In general, the anterior horns of both medial and lateral menisci were less affected by age and OA. Conclusions New standardized protocols and new validated grading systems allowed us to conduct a more systematic evaluation of changes in aging and OA menisci at a macroscopic and microscopic level. Several meniscus abnormalities appear to be specific to aging in the absence of significant OA. With aging the meniscal surface can be intact but abnormal matrix organization and cellularity was observed within the meniscal substance. The increased Safranin-O staining appears to represent a shift from fibroblastic to chondrocytic phenotype during aging and early degeneration.

Arthroscopic SCR restored superior glenohumeral stability and improved shoulder function among patients with or without pseudoparalysis who had previously irreparable rotator cuff tears. In the absence of postoperative graft tear, arthroscopic SCR reversed preoperative pseudoparalysis. Graft healing rates after arthroscopic SCR did not differ between patients with and without pseudoparalysis.

Objective The development and patterns of spontaneous aging-related changes in the anterior cruciate ligament (ACL) and their relationship to articular cartilage degeneration are not well characterized. The aim of this study was to investigate the types and temporal sequence of aging-related ACL changes and establish the correlation with cartilage lesion patterns at all stages of OA development in human knee joints without prior joint trauma. Methods Human knee joints (n=120; 65 donors; age 23-92) were obtained at autopsy and ACL and cartilage were graded macroscopically and histologically. Inflammation surrounding the ACL was assessed separately. Results Histological ACL substance scores and ligament sheath inflammation scores increased with aging. Collagen fiber disorganization was the earliest and most prevalent change. The severity of mucoid degeneration and chondroid metaplasia in the ACL increased with development of cartilage lesions. A correlation between ACL and cartilage degeneration was observed, especially in the medial compartment of the knee joint. Conclusion ACL degeneration is highly prevalent in knees with cartilage defects, and may even precede cartilage changes. Hence, ACL deficiencies may not only be important in post-traumatic OA, but also a feature associated with knee OA pathogenesis in general.

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