Aggrecan plays a crucial role in the ability of tissues to withstand compressive loads during the pathological progression of osteoarthritis (OA). Progressive loss of aggrecan from cartilage may result in exposure of the collagen matrix and can lead to its disintegration by metalloproteases. Although aggrecanases are expressed constitutively in human chondrocytes, the degradation of aggrecan is induced by proinflammatory cytokines; however, little is known about the underlying mechanisms. Human primary chondrocytes from OA patients or healthy donors and human chondrogenic SW1353 cells were cultured and stimulated with IL-1β in vitro, the mRNA expressions and protein levels of MMP-13, ADAMTS-4, ADAMTS-5, SENP1, and SENP2 were determined using real time PCR and Western blot, respectively. The localizations of aggrecan and Col-II, as well as the SUMOylation modification of these proteins were analyzed using immunofluorescence and immunoprecipitation assays, respectively. Our results showed that a proinflammatory cytokine interleukin-1β induced the OA model and desumoylation of aggrecan and collagen type II because the small ubiquitin-like modifier 2/3 (SUMO2/3) was co-localized with aggrecan and collagen type II proteins and interacted physically with them. Mechanistic studies have shown that knockdown of SUMO2/3 expression can significantly enhance the rate of degradation of aggrecan and collagen type II at both the mRNA and protein levels in the OA model. In addition, SUMO-specific protease 2 (SENP2) plays important roles in the desumoylation of aggrecan, while knockdown of SENP2 can protect aggrecan and collagen type II. Clinical assays have shown that OA patients have higher SENP2 levels than healthy controls, and the SENP2 level correlates negatively with both aggrecan and collagen type II levels. SENP2 desumoylates aggrecan and collagen type II proteins in the inflammation induced OA, and SENP2 expression correlates with OA progression.