Bone Abstracts

Osteoblasts line the inner surface of the bone and are located in close proximity to the bone marrow, where hematopoiesis takes place. Osteoblasts produce several cytokines that affect various steps of hematopoiesis, and produce fibronectin isoforms that affect cell differentiation. Little is known however on whether osteoblasts modulate the immune response. Our aim was to evaluate the role of fibronectin originating from the osteoblasts on hematopoiesis and the immune response to cancer.

Using conditional deletion of fibronectin in differentiating osteoblasts (Col-alpha1(I)-cre/+_fibronectin^{floxed/floxed}: cKO) we detected a decrease in the percentage of myeloid cells (CD11b+) by 28% (P<0.05) in the bone marrow. In transplantation experiments, followed by cocultures of bone marrow with control (CT) and cKO osteoblasts, we confirmed that the decrease in myeloid cells was only present when using cKO osteoblasts. Addition of three isoforms of fibronectin produced by osteoblasts allowed the attribution of the change in myeloid cells to the production of the isoform called EDA-fibronectin by the osteoblasts.

Cancer growth of the breast cancer cell line MDA-MB-231/luc in cKO was diminished as evidenced by increased survival (by 14%, P<0.05) and decreased growth (by 18–35%) after intracardiac and intratibial injection.

In order to determine whether this was due to a change in myeloid cell function we isolated these cells from bone marrow, determined their cytokine profile and found that arginase-1 was increased in cells exposed to EDA. Adoptive transfer experiments showed that EDA-fibronectin stimulated arginase-1 expression in myeloid cells and hence cancer growth, and inhibiting EDA effects by interfering with the mediating receptor, or preexposure to arginase-1-inhibitor prevented the EDA-mediated enhancement of cancer growth.

In summary, EDA fibronectin produced by the osteoblasts increases arginase-1 expression which in turn suppresses the immune response against cancer. Preventing osteoblastic-EDA effects, on the other hand, improves the immune response against cancer and diminishes its growth. These findings suggest new possibilities in the modulation of the immune response against cancer.