Thyroid hormones induce features of the hypertrophic phenotype and stimulate correlates of CPPD crystal formation in articular chondrocytes

Objective, Articular cartilage affected by calcium pyrophosphate dihydrate (CPPD) crystal deposition contains abnormal chondrocytes with morphologic s imilarities to the terminally differentiated hypertrophic chondrocytes that mineralize in growth plate cartilage. These chondrocytes also elaborate hi gh levels of extracellular inorganic pyrophosphate (PPI), an essential comp onent of the CPPD crystal. Several factors that stimulate articular chondro cyte PPi elaboration also induce terminal differentiation in growth plate c hondrocytes. We hypothesized that factors such as thyroid hormones (T3 and T4) that are potent stimulants of growth plate chondrocyte hypertrophy migh t also stimulate articular chondrocyte hypertrophic differentiation. We als o hypothesized that like transforming growth factor-beta (TGF-beta), ascorb ate, and retinoic acid, thyroid hormones would increase chondrocyte PPi ela boration. Methods. We determined the effects of T3, T4, and TGF-beta on markers of th e hypertrophic phenotype such as alkaline phosphatase (ALPase) activity and type X collagen production; and the effects of T3 and T4 on processes impl icated in CPPD crystal formation including PPi elaboration and nucleoside t riphosphate pyrophosphohydrolase (NTPPPH) activity in adult porcine articul ar chondrocytes in culture, Results, ALPase activity increased 3-fold with T3 and T4 and 1.3-fold with TCF-beta. Type X collagen levels also increased with thyroid hormone treatm ent. [I-125]T3 binding studies proved the existence of saturable T3 recepto rs on chondrocytes. Media [PPi] and cellular NTPPPH activity significantly increased in cultures treated with 1-10 nM T3 or 100-500 nM T4. Conclusion. Increased PPi elaboration is an additional and previously unrec ognized feature of hypertrophic differentiation in articular chondrocytes. These terminally differentiated chondrocytes may play a pathogenic role in CPPD crystal deposition disease.