Proposed signalling interactions between C-type natriuretic peptide (CNP) and mechanical loading in chondrocytes. CNP primarily activates natriuretic peptide (Npr)2 which underlies guanylyl cyclase (GC) activity and mediates several cell-signalling effects through the synthesis of 3,5-cyclic guanosine monophosphate (cGMP) and membrane-bound cyclic GMP-dependent protein kinase II (PKGII). It has been reported that the Gi/o binding domain in Npr3 activates extracellular-signal-regulated kinase 1/2 (ERK 1/2) or the phospholipase C (PLC) and inosital triphosphate (IP3) pathway via adenylate cyclase/cAMP inhibition. PLC activation and IP3 generation is well known to contribute to Ca2+ release from intracellular stores. This pathway supports cartilage homeostasis by mediating the anabolic effects involved in mechanotransduction. Furthermore, mechanical signals stimulate Npr expression and CNP levels, which mediates anabolic effects involving extracellular matrix (ECM) synthesis. In contrast, IL-1β stimulates catabolic activities via inducible nitric oxide synthase (iNOS) and nitric oxide (NO)/sGC/cGMP levels. The IL-1β-induced catabolic response could be inhibited by mechanosensitive CNP or Ca2+ release through stretch-activated ion channels or integrin-mediated signals involving F-actin/cytoskeletal reorganisation.