ABSTRACT
OBJECTIVE: Defects in autophagy contribute to joint aging and Osteoarthritis (OA). Identifying specific autophagy types could be useful for developing novel treatments for OA. DESIGN: An autophagy-related gene array was performed in blood from non-OA and knee OA subjects from the Prospective Cohort of A Coruña (PROCOAC). The differential expression of candidate genes was confirmed in blood and knee cartilage and a regression analysis was performed adjusting for age and BMI. HSP90A, a chaperone mediated autophagy (CMA) marker was validated in human knee joint tissues, as well as, in mice with aging-related and surgically-induced OA. The consequences of HSP90AA1 deficiency were evaluated on OA pathogenesis. Finally, the contribution of CMA to homeostasis was studied by assessing the capacity to restore proteostasis upon ATG5-mediated macroautophagy deficiency and genetic HSP90AA1 overexpression. RESULTS: 16 autophagy-related genes were significantly down-regulated in blood from knee OA subjects. Validation studies showed that HSP90AA1 was down-regulated in blood and human OA cartilage and correlated with risk incidence of OA. Moreover, HSP90A was reduced in human OA joints tissues and with aging and OA in mice. HSP90AA1 knockdown was linked to defective macroautophagy, inflammation, oxidative stress, senescence and apoptosis. However, macroautophagy deficiency increased CMA, highlighting the CMA-macroautophagy crosstalk. Remarkably, CMA activation was sufficient to protect chondrocytes from damage. CONCLUSIONS: We show that HSP90A is a key chaperone for chondrocyte homeostasis, while defective CMA contributes to joint damage. We propose that CMA deficiency is a relevant disease mechanism and could represent a therapeutic target for OA.
Subject(s)
Cartilage, Articular , Chaperone-Mediated Autophagy , Osteoarthritis, Knee , Humans , Mice , Animals , Osteoarthritis, Knee/pathology , Prospective Studies , Cartilage, Articular/pathology , Aging/genetics , Knee Joint/pathology , Autophagy/genetics , Chondrocytes/metabolismABSTRACT
The importance of colorectal cancer (CRC) is increasing. A proportion show a hereditary component, as in Lynch syndrome and Familial Adenomatous Polyposis, and a recently defined entity as well, namely, Familial Colorectal Cancer type X. The high probability to develop CRC in these groups may, at the time of recognition, change surgical management, including its timing or even the surgical technique. In some cases prophylactic surgery can play an important role. The possibility of using tools that allow recognition of the aforementioned syndromes, including microsatellite instability, immunohistochemistry for DNA mismatch repair system proteins, and especially their mutations, is on the basis of therapeutic strategies that differ from those employed in sporadic CRC cases.
Subject(s)
Adenomatous Polyposis Coli/surgery , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/surgery , Colorectal Neoplasms/genetics , Colorectal Neoplasms/surgery , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Adult , Age Factors , Colectomy , Colonoscopy , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , DNA Mismatch Repair , Female , Genetic Counseling , Humans , Immunohistochemistry , Male , Microsatellite Instability , Mutation , Pedigree , Proctocolectomy, RestorativeABSTRACT
The importance of colorectal cancer (CRC) is increasing. Aproportion show a hereditary component, as in Lynch syndromeand Familial Adenomatous Polyposis, and a recently defined entityas well, namely, Familial Colorectal Cancer type X. The highprobability to develop CRC in these groups may, at the time ofrecognition, change surgical management, including its timing oreven the surgical technique. In some cases prophylactic surgerycan play an important role. The possibility of using tools that allowrecognition of the aforementioned syndromes, including microsatelliteinstability, immunohistochemistry for DNA mismatchrepair system proteins, and especially their mutations, is on thebasis of therapeutic strategies that differ from those employed insporadic CRC cases(AU)
Subject(s)
Humans , Male , Female , Adult , Colonic Neoplasms/congenital , Colonic Neoplasms/diagnosis , Colonic Neoplasms/surgery , Rectal Neoplasms/diagnosis , Rectal Neoplasms/surgery , Biomarkers/analysis , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/surgery , Colectomy/methods , Anastomosis, Surgical/methods , Rectal Neoplasms/genetics , Molecular Biology/methods , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/physiopathology , Biopsy/methods , Colonoscopy/methodsABSTRACT
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