Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis.
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.



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.



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.



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.
The Scripps Research Institute, La Jolla, California.
Oscar
O
Alvarez-Garcia
The Scripps Research Institute, La Jolla, California.
Tokio
T
Matsuzaki
The Scripps Research Institute, La Jolla, California.
Merissa
M
Olmer
The Scripps Research Institute, La Jolla, California.
Lars
L
Plate
The Scripps Research Institute, La Jolla, California.
Jeffery W
JW
Kelly
The Scripps Research Institute, La Jolla, California.
Martin K
MK
Lotz
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D001678:Organelle Biogenesis; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*
D000071187:Autophagy-Related Protein 5; D004268:DNA-Binding Proteins; C469992:Ddit4 protein, mouse; D006609:High Mobility Group Proteins; C490547:MAP1A protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C081930:Tfam protein, mouse; D014157:Transcription Factors; C085284:microtubule-associated protein 1B; D055372:AMP-Activated Protein Kinases