Signals induced by mechanical loading and C-type natriuretic peptide (CNP) represent chondroprotective routes that may potentially prevent osteoarthritis (OA). We examined whether CNP will reduce hyaluronan production and export via members of the multidrug resistance protein (MRP) and diminish proinflammatory effects in human chondrocytes. The presence of interleukin-1 beta (IL-1 beta) increased HA production and export via MRP5 that was reduced with CNP and/or loading. Treatment with IL-1 beta conditioned medium increased production of catabolic mediators and the response was reduced with the hyaluronan inhibitor, Pep-1. The induction of pro-inflammatory cytokines by the conditioned medium was reduced by CNP and/or Pep-1, alpha CD44 or alpha TLR4 in a cytokine-dependent manner, suggesting that the CNP pathway is protective and should be exploited further. (C) 2015 Elsevier Inc. All rights reserved.