Osteocrin, a peptide secreted from the heart and other tissues, contributes to cranial osteogenesis and chondrogenesis in zebrafish

Abstract

The heart is an endocrine organ, because cardiomyocytes (CMs) secrete natriuretic peptide (NP) hormones. Since the discovery of NPs, no peptide hormones that affect remote organs have been identified from the heart. We identified osteocrine (Ostn) as an osteogenesis/chondrogenesis regulatory hormone secreted from CMs in zebrafish. The ostn mutant larvae exhibited impaired membranous and chondral bone formation. The impaired bones were recovered by CM-specific overexpression of Ostn. We analyzed parasphenoid (ps) as a representative of membranous bones. In the shortened ps of the ostn morphants, nuclear Yap1/Wwtr1-dependent transcription was increased, suggesting that Ostn might induce the nuclear export of Yap1/Wwtr1 in osteoblasts. Although OSTN is proposed to bind to NPR3 (clearance receptor for NPs) to enhance the binding of NPs to NPR1 or NPR2, OSTN enhanced C-type NP-dependent nuclear export of YAP1/WWTR1 of cultured osteoblasts stimulated with saturable CNP. OSTN, therefore, might activate unidentified receptors that augment protein kinase G signaling mediated by a CNP-NPR2 signaling axis. These data demonstrate that Ostn secreted from the heart contributes to bone formation as an endocrine hormone.