Piezo2 Expressed in Proprioceptive Neurons is Essential for Skeletal Integrity

In humans, mutations in the PIEZO2 gene, which encodes for a mechanosensitive ion channel, were found to result in skeletal abnormalities including scoliosis and hip dysplasia. However, this gene is widely expressed throughout the body and the contribution of tissue-specific expression to the phenotypes remained elusive. In this work, we show in mice that loss of Piezo2 expression in the proprioceptive system recapitulates the human skeletal abnormalities.

Utilizing mouse genetics, we show that loss of Piezo2 in chondrogenic or osteogenic lineages do not lead to a skeletal phenotype. By contrast, loss of Piezo2 in proprioceptive neurons led to spine misalignment and hip dysplasia, suggesting a non-autonomous role for Piezo2 and the proprioceptive system in skeletal regulation. To validate the role of proprioception in hip joint morphogenesis, we studied this process in mice mutant for Runx3 or Egr3, transcription factors that are necessary for the ontogenesis of this system. Loss of Runx3 in the peripheral nervous system, but not in skeletal lineages, led to similar joint abnormalities, as did Egr3 loss of function, which strongly confirms the involvement of proprioception in hip joint integrity.

These findings expand the range of known regulatory roles of the proprioception system on the skeleton. Moreover, by showing the importance of Piezo2 expression in the proprioceptive system for this regulation, our findings provide the first component of the underlying molecular mechanism.