Deletion ofFibroblast growth factor 9globally and in skeletal muscle results in enlarged tuberosities at sites of deltoid tendon attachments

The growth of most bony tuberosities, like the deltoid tuberosity (DT), rely on the transmission of muscle forces at the tendon-bone attachment during skeletal growth. Tuberosities distribute muscle forces and provide mechanical leverage at attachment sites for joint stability and mobility. The genetic factors that regulate tuberosity growth remain largely unknown. In mouse embryos with global deletion offibroblast growth factor 9(Fgf9), the DT size is notably enlarged. In this study, we explored the tissue-specific regulation of DT size using both global and targeted deletion ofFgf9. We showed that cell hypertrophy and mineralization dynamics of the DT, as well as transcriptional signatures from skeletal muscle but not bone, were influenced by the global loss ofFgf9. Loss ofFgf9during embryonic growth led to increased chondrocyte hypertrophy and reduced cell proliferation at the DT attachment site. This endured hypertrophy and limited proliferation may explain the abnormal mineralization patterns and locally dysregulated expression of markers of endochondral development inFgf9^nullattachments. We then showed that targeted deletion ofFgf9in skeletal muscle leads to postnatal enlargement of the DT. Taken together, we discovered thatFgf9may play an influential role in muscle-bone crosstalk during embryonic and postnatal development.