Primordial cartilage serves as the skeletal template during development. It gives rise to two types of cartilage, growth cartilage and articular cartilage, after birth. Growth cartilage is where the bone grows in children, and its dysfunction due to genetic mutations causes short stature and skeletal malformation, conditions called skeletal dysplasia. Articular cartilage covers the ends of bones and provides shock absorption and lubrication to diarthrodial joints. Injury and degeneration of articular cartilage cause joint pain during motion, leading to osteoarthritis in adults. The conditions that compromise growth cartilage or articular cartilage are poorly understood, and curative drugs are not available. iPSC technologies have been used to study cartilage diseases. Cartilage consists of chondrocytes embedded in abundant extracellular matrix that the chondrocytes produce. We have developed a method in which human iPSCs (hiPSCs) are differentiated toward chondrocytes that produce extracelluar matrix to prepare cartilage (hiPSC-derived cartilage).

We are generating effective and safe hiPSC-derived cartilage as regenerative medicine technology to treat damage in articular cartilage and sustain healthy joint function. The goal is to use this cartilage in clinical tests. Currently, we are performing pre-clinical tests by transplanting iPSC-derived cartilage into defects created in the articular cartilage of model animals. We are also analyzing the molecular mechanisms that regulate chondrocyte differentiation and cartilage homeostasis. We have clarified that salt-inducible kinase 3 (SIK3) regulates the differentiation of chondrocytes and maintenance of articular cartilage. SIK3 can be a target molecule for treating articular cartilage damage.

In a separate project, we have generated hiPSC-derived cartilage from patients with skeletal dysplasia. FGFR3 chondrodysplasia such as achondroplasia is caused by a gain-of-function mutation in the FGFR3 gene. We found that chondrocytes derived from hiPSCs generated from patients suffering from FGFR3 chondrodysplasia produce abnormal cartilage that reproduces the pathology of the diseases and thus offers an iPSC-based disease model.