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Significance Skeletal diseases place a huge burden on patients and society, and yet their genetic basis remains poorly understood. In this article, we identify Speckle-type POZ protein (Spop) as a regulator of skeletal development, loss of which leads to shorter digit bones and lower bone density. We also show that, in striking contrast to the current dogma positing Spop as a negative regulator of Hedgehog (Hh) signaling, Spop regulates skeletal development by promoting Indian Hedgehog (Ihh) signaling. Therefore, our work represents an important conceptual advance in the understanding of Ihh signaling and skeletal development and provides a potential new target for the diagnosis and intervention of bone diseases such as osteoporosis.

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling