Osteoporosis and osteoblasts cocultured with adipocytes inhibit osteoblast differentiation by downregulating histone acetylation.

Osteoporosis is characterized by decreased bone mass and adipocyte accumulation within the bone marrow that inhibits osteoblast maturation, leading to a high risk of fractures. Thus, we hypothesized that osteoblasts, besides being negatively affected by interacting with adipocytes, reduce the differentiation of neighboring osteoblasts through the same mechanisms that affect osteoblasts under osteoporotic conditions. We investigated the effect of osteoporosis on osteoblast differentiation and the effect of the conditioned medium of osteoblasts cocultured with adipocytes on the differentiation of other osteoblasts. Osteoporosis was induced by orchiectomy in rats and bone marrow mesenchymal stromal cells (MSCs) were differentiated into osteoblasts. Also, the bone marrow and adipose tissue MSCs were obtained from healthy rats and differentiated into osteoblasts and adipocytes, respectively. Messenger RNA expression, in situ alkaline phosphatase activity, and mineralization confirmed the inhibitory effect of osteoporosis on osteoblast differentiation. This harmful effect was mimicked by the in vitro model using the conditioned medium and it was demonstrated that osteoblasts keep the memory of the negative impact of interacting with adipocytes, revealing an unknown mechanism relevant to the osteoporotic bone loss. Finally, we showed the involvement of acetyl-histone 3 (AcH3) in bone homeostasis as its reduction induced by osteoporosis and conditioned medium impaired osteoblast differentiation. The AcH3 involvement was proved by treating osteoblasts with Trichostatin A that recovered the AcH3 expression and osteoblast differentiation capacity in both situations. Together, our findings indicated that AcH3 might be a target for future studies focused on epigenetic-based therapies to treat bone diseases.