Identification of calponin 3 as a novel Smad-binding modulator of BMP signaling expressed in cartilage

Bone morphogenetic proteins (BMP) play a prominent role in cartilage tissue homeostasis and perturbations of BMP signaling contribute to pathological processes like osteoarthritis. The response to BMP is determined by intracellular proteins interacting with the signal mediators Smads 1 and 5. Applying the yeast two-hybrid technique we could identify the actin-binding protein calponin 3 as a novel Smad-binding protein expressed in chondrocytes. It interacted with Smads 1 and 5 and overexpression led to an attenuation of BMP-dependent transcription. Calponin 3 mRNA and protein were expressed in cartilage tissue and isolated chondrocytes and a slight, but statistically significant reduction of mRNA expression levels could be detected in osteoarthritic cartilage. Our results suggest a role of calponin 3 in the regulation of BMP-dependent cellular responses. By interaction with the Smad proteins 1 and 5 and the inhibition of BMP-induced transcription, calponin 3 provides a negative regulatory mechanism for the BMP signaling pathway. This inhibitory effect likely depends on a sequestration of the Smads to the cytoskeleton due to the actin-binding properties of calponin 3. The down-regulation of calponin 3 expression in osteoarthritic joints could contribute to the increased responsiveness to BMPs described previously. Furthermore, our data provide a possible explanation for the effect of the related protein calponin 1 on bone and cartilage development.