{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T19:41:47Z","timestamp":1783712507810,"version":"3.55.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2013,12,19]],"date-time":"2013-12-19T00:00:00Z","timestamp":1387411200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2013,12,19]],"date-time":"2013-12-19T00:00:00Z","timestamp":1387411200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Excess C\/EBP homologous protein (CHOP) expression is one feature of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress. Here, we focused on CHOP expression and function in chondrocytes.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>We studied human knee osteoarthritis (OA) cartilage, bovine chondrocytes cultured in alginate and subjected to sub-lethal biomechanical injury, and knee chondrocytes of human autopsy donors. We performed siRNA knockdown and transfection.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>UPR activation was increased in human knee OA cartilage <jats:italic>in situ<\/jats:italic>, and in biomechanically injured cultured chondrocytes <jats:italic>in vitro<\/jats:italic>. In normal human chondrocytes, CHOP \u201cgain of function\u201d sensitized chondrocytes to IL-1\u03b2 induced nitric oxide (NO) and matrix metalloproteinase (MMP)-3 release without inducing these responses by itself. Excess CHOP expression, by itself, induced superoxide production and apoptosis. Conversely, siRNA knockdown of CHOP and the UPR-specific mediator X-box binding protein (XBP1) inhibited NO release by &gt;80% (<jats:italic>P<\/jats:italic> &lt;0.0005) in response to IL-1\u03b2, and blunted MMP-3 release, whereas there were only minimal effects of the UPR mediator GRP78 on these responses. The anti-inflammatory metabolic \u201csuper-regulator\u201d AMP kinase (AMPK) is known to limit UPR activation in vascular muscle cells. Here, CHOP supported the capacity of IL-1\u03b2 to suppress AMPK activity in chondrocytes. We also observed that inhibition of AMPK activity promoted an increase in chondrocyte CHOP expression. Conversely, pharmacologic activation of AMPK by 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) blunted chondrocyte CHOP expression in response to biomechanical injury.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>Biomechanical injury and IL-1 signaling stimulate UPR activation in chondrocytes. CHOP mediates chondrocyte catabolic and apoptotic responses to IL-1\u03b2, and does so partly by inhibiting AMPK activity. Conversely, development of excess CHOP activity is limited by AMPK activity in chondrocytes. Our findings suggest a mechanism for potential chondroprotection by AICAR and other AMPK activators. The work is of translational relevance for OA, since several drugs that activate AMPK are already in the clinic for arthritis (for example, allosteric AMPK activators sodium salicylate and high dose aspirin, and methotrexate, which activates AMPK by generating AICAR).<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar4415","type":"journal-article","created":{"date-parts":[[2013,12,19]],"date-time":"2013-12-19T11:25:40Z","timestamp":1387452340000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["C\/EBP homologous protein drives pro-catabolic responses in chondrocytes"],"prefix":"10.1186","volume":"15","author":[{"given":"Matt","family":"Husa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freyr","family":"Petursson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Terkeltaub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Liu-Bryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,12,19]]},"reference":[{"key":"4083_CR1","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1177\/1759720X12448454","volume":"4","author":"MB Goldring","year":"2012","unstructured":"Goldring MB: Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. 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