Most vertebrate bones develop through endochondral ossification. During this process, proliferating chondrocytes form a cartilage scaffold, differentiate into hypertrophic chondrocytes and die. The cartilage scaffold is then degraded and replaced by bone. Chondrocyte hypertrophy is, therefore, crucial for endochondral ossification. On , Noriyuki Tsumaki and colleagues identify salt-inducible kinase 3 (SIK3) as an essential factor for chondrocyte hypertrophy in mice. SIK3-deficient mice, the researchers report, exhibit dwarfism, bone malformation and accumulation of chondrocytes in various bones. These phenotypes, they suggest, are due to impaired chondrocyte hypertrophy. Consistent with this suggestion, SIK3 is expressed in prehypertrophic and hypertrophic chondrocytes in the embryonic bones and postnatal growth plates of wild-type mice. Other experiments show that SIK3 anchors histone deacetylase 4 (HDAC4) in the cytoplasm, thereby releasing MEF2C, a transcription factor that facilitates chondrocyte hypertrophy, from suppression by HDAC4 in the nucleus. These results suggest that the regulation of HDAC4 by SIK3 is important for the progression of chondrocyte hypertrophy during skeletal development.
