BMP2 signalling activation enhances bone metastases of non-small cell lung cancer.

Distant metastases occur when non-small cell lung cancer (NSCLC) is at late stages. Bone metastasis is one of the most frequent metastases of NSCLC and leads to poor prognosis. It has been reported that high expression of BMP2 in NSCLC correlates with poor survival, but whether BMP2 contributes to NSCLC bone metastasis remains largely unknown. The activation of BMP signalling is found in metastatic bone tumours of mice Lewis lung carcinoma and predicts poor survival in human NSCLC. BMP2 signalling activation can enhance bone metastasis of Lewis lung carcinoma. Moreover, BMP2 secreted by stroma fibroblasts can promote the migration and invasion of NSCLC cells. Besides, in combination with pre-osteoblast and LLCs, BMP2 could enhance the differentiation of macrophages into osteoclasts to play roles in the osteolytic mechanism of NSCLC bone metastasis. Interestingly, NSCLC cells can also enrich BMP2 to pre-osteoblasts to function in the osteoblastic mechanism. Our results firstly demonstrate the detailed mechanisms about what roles BMP2 signalling play in enhancing NSCLC bone metastases. These findings provide a new potential therapy choice for preventing bone metastases of NSCLC via the inhibition of BMP2 signalling.

Bone morphogenetic protein 2/SMAD signalling in human ligamentocytes of degenerated and aged anterior cruciate ligaments.

OBJECTIVE: Anterior cruciate ligament (ACL) degeneration leads to knee instability and favors osteoarthritis (OA) progression. During ageing the growth factor sensitivity of ligaments changes but nothing is known about BMP2-signalling and -sensitivity in degenerated ACLs. This study addressed the question whether a dysregulated BMP2 signalling might contribute to age- and OA-dependent ACL degeneration. METHOD: ACL samples from patients with/without OA of different ages (<60 and ≥60 years, males, females) were graded histopathologically (n = 45). After stimulation of cultured ACL fibroblasts with 5 nM BMP2 for different time points, phosphorylation of SMAD1/5/8 and gene expression of crucial BMP2 signalling proteins, ligamentogenic and chondrogenic transcription factors, scleraxis (SCX) and SOX9, were analyzed. RESULTS: ACL samples displayed different grades of degeneration, often associated with synovitis and calcium deposits. Degeneration correlated significantly with synovitis. ACL fibroblasts expressed BMP type I receptors ALK3 and ALK6 and the BMP type II receptor BMPRII. Donors could be divided into "responders" and "non responders" since their BMP2 mediated SMAD1/5/8 phosphorylation level differed. Basal ID1 expression was lower in cells derived from OA compared with non-OA patients and BMP2 led to an ID1 induction in both. Irrespective of BMP2 stimulation, the donor age significantly influenced the expression profile of BMP6 and SCX but not BMP signalling. The BMP2-mediated SMAD6 expression differed between OA and healthy ACL fibroblasts. CONCLUSION: Our data indicate that the expression level of BMP2/SMAD target genes such as ID1 and SMAD6 was reduced in ACL fibroblasts derived from OA compared with non OA patients.