Despite its solid structure, bone is very dynamic, with cells constantly degenerating and regenerating. Imbalance in these two processes can damage bone and is typical with age and several bone diseases. The research team of CiRA Orthopedic Surgeon Junya Toguchida reports a method to prepare bone nodules from human iPS cells. The researchers use the nodules to reveal key factors in bone regeneration and to explore drug candidates for osteogenesis imperfecta, a congenital bone disease.

According to Toguchida, bone nodules are the gold standard to study how cells form bones, but with one caveat.

"Precursor cells are induced into osteoblasts, which form bone matrix proteins. Visualizing the process from human precursor cells is difficult," he notes.

The new study reports that modifying the concentration of retinoic acid in a standard protocol accelerated the formation of bone nodules from human iPS cells to 10 days, which is less than half the time otherwise.

The faster time makes imaging of the development easier. "Observing the migration of the cells and their transition from osteoblasts to osteocytes will help us understand disease development," says Toguchida.

Indeed, the researchers found retinoic acid amplified the expression of genes associated with bone formation in the nodules, whereas its absence left the nodules immature.

To test the benefits of this system for disease modeling, the researchers prepared iPS cells from two patients with osteogenesis imperfecta, a rare disease that causes extreme bone fragility due to defects in connective tissue. The bones formed from these iPS cells were abnormal in their expression of collagen I, a major matrix protein. Treatment of the cells with a drug candidate could recover collagen I expression and improve the nodule formation.

Additional study found which cell receptors the retinoic acid acted on to promote the bone formation from iPS cells, providing potential drug targets to promote bone growth independent of disease.

"The most important advantage of our system is that it can be applied to drug screenings. It lowers time and cost and with iPS cells we can study a large number of bone diseases," says Toguchida.

• doi: 10.1038/s41551-019-0410-7