Ageing increases growth factor-induced inorganic pyrophosphate elaboration by articular cartilage

Advanced age is the most common risk factor for the development of calcium pyrophosphate dihydrate (CPPD) crystal-associated arthritis. However, the link between ageing and CPPD crystal formation in cartilage remains unexplained. In CPPD deposition disease, excess extracellular inorganic pyrophosphate (ePPi), generated by articular chondrocytes, accumulates in affected joints and contributes to CPPD crystallogenesis. Transforming growth factor beta 1 (TGF beta 1) is the first known physiologic stimulant of ePPi elaboration by adult porcine and human cartilage. We hypothesized that sensitivity of articular cartilage to the ePPi-stimulatory effects of TGF beta 1 may increase with ageing. Accordingly, we compared the effects of TGF beta 1 on cartilage ePPi elaboration from juvenile, young adult, and old adult pigs. Cartilage organ cultures from old animals increased ePPi elaboration in response to TGF beta 1 to a greater extent than did cartilage from juvenile and young adult animals. Similar results were seen in chondrocyte monolayers. Concurrent exposure to epidermal growth factor (EGF) augmented, but was not necessary for TGF beta 1-induced ePPi elaboration by adult cartilage. In contrast, in juvenile cartilage, concurrent exposure to EGF was required to permit TGF beta 1-induced ePPi elaboration. Thus, increased cartilage responsiveness to the ePPi-stimulatory effects of TGF beta 1 occurs with ageing, and may explain the link between advanced age and CPPD deposition disease.