ECTS Abstracts (2015) 1 OC5.3

MUC1 in osteoblasts balances osteogenesis and angiogenesis under hypoxia

Jyotirmaya Behera1,2, Andrea Brum1, Marijke Schreuders-Koedam1, Cindy van der Leije1, Suvro Chatterjee2, Johannes van Leeuwen1 & Bram van der Eerden1

1Erasmus MC, Internal Medicine, Rotterdam, The Netherlands; 2AU-KBC Research Centre, Anna University, Chennai, India.

It is critical that bone formation and angiogenesis are tightly coordinated during bone development and fracture healing. Oxygen tension impacts both processes. Previously we demonstrated that hypoxia limits osteoblast differentiation/mineralisation and strongly induces mucin1 (MUC1) expression in human osteoblasts. Expression of MUC1 is positively associated with hypoxia-driven angiogenesis. Thereby MUC1 is a likely candidate to control both osteogenesis and angiogenesis. We investigated MUC1 function in osteoblasts and its role in the interaction between bone formation and angiogenesis. Hypoxia (2% O2)-induced inhibition of osteoblast differentiation (Alkaline phosphatase activity −64%) and mineralisation (−89%) was prevented by blocking MUC1 function using either a specific inhibitor (GO-201) or 2 shRNAs. This was supported by studies using osteoblasts cultured from bone marrow of Muc1 knockout mice. Conditioned medium of osteoblasts cultured under hypoxia (HCM) stimulated endothelial migration (+80%) and angiogenesis (+150%), which was prevented by blocking MUC1 in osteoblasts using GO-201 or shRNA. Mass spectrometry analysis identified among others vascular endothelial growth factor (VEGF)-A and macrophage migration inhibitory factor (MIF) to be present in control HCM but not in HCM of osteoblasts treated with GO-201 and shRNA. VEGF neutralising antibody or MIF inhibitor 4-IPP prevented HCM-induced endothelial morphogenesis. HCM induced nitric oxide (NO) production (1.8-fold increase) in human endothelial cells and inhibition of NO production blocked the angiogenic effect of HCM. Finally, it was shown that nuclear translocation of the MUC1 cytoplasmic tail in osteoblasts is essential for the effects observed. In conclusion, we demonstrate that MUC1 in osteoblasts is at the crossroad of oxygen control of osteoblast differentiation/mineralisation and angiogenesis. The level and nuclear translocation of MUC1 in osteoblasts determines whether under hypoxia either bone formation or angiogenesis prevails. Thereby, these data contribute to the molecular understanding of the balance between osteogenesis and angiogenesis in bone development and fracture repair.

Disclosure: The authors declared no competing interests. This work was supported by the European Union (PIRSES-GA-2011-295181).

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