BMP-SMAD (bone morphogenetic protein) signaling pathways in association with APT play paramount roles in osteoblastic differentiation, bone formation and embryonic development of human and animals. However, the implications of potent components (BMP6, Smad1, Smad2 and APT) of this pathway in SCD (sickle cell disease) pathology with orthopedic complications (Ortho + SS) are poorly elucidated and substantially unknown. Here, we address the role of BMP6, Smad1, Smad2 and APT mRNA and protein expression in hMDDCs obtained from Ortho + SS patients, employing RT-PCR, qRT-PCR and immunoblotting. Interestingly, we observed that SCD pathology exhibited significantly up-regulated expression of those signaling components at the level of mRNA and protein. Furthermore, exogenous BMP6 induced apoptosis was observed to be significantly associated in Ortho + SS complication and markedly increased the percentage of cells undergoing apoptosis as compared to healthy group. Interestingly, the non-stimulated cells have shown higher apoptotic nuclei percentage than the stimulated cells in pathological condition. Thus, expression of BMP-SMAD signaling components augments apoptosis and up regulates the transcription of these genes and it suggests that induction is due to transcriptional regulation. Taken together, our findings provide evidence that BMP-SMAD signaling components along with APT were over expressed, mediates apoptosis and may play an important role in the SCD pathology with orthopedic complications. (C) 2010 Elsevier Inc. All rights reserved.