MON-LB086 Single-Cell Transcriptional Profiling of Bone Cells Reveals Diversity of Osteoblasts

Recent studies using mouse genetics have revealed that, beyond ambulation, protection and ion homeostasis, bone plays an unexpected broader role in whole-organism physiology as an endocrine organ. The osteoblast-derived hormone osteocalcin (Ocn) is necessary for glucose homeostasis, insulin secretion, male fertility, brain development, cognition and adaptation to exercise (1,2). However, it remains unknown whether the diversity of bone’s functions is built upon diversity in osteoblast subtypes. Here, we perform single-cell RNA-seq to explore the diverse physiological functions of osteoblasts. While all osteoblasts expressed equally high levels of classically osteogenic genes like Runx2, and Type I Collagen, our analysis identified four transcriptionally distinct osteoblast populations. Strikingly, one osteoblast population expresses Ocn as well as several other genes, including vitamin D receptor Vdr and Wnt signaling modulator Dkk1, all of which have been implicated in osteoblasts as negative regulators of bone mass control (3,4,5). In contrast, other osteoblast populations are enriched for bone mineralization genes, voltage-gated ion channels, postsynaptic markers, and neurotrophic factors, while the Ocn high population is not. These molecular signatures further establish the neuroendocrine function of osteoblasts, which is further supported by the role of Ocn in the response to acute stressors, immunohistochemistry of postsynaptic markers in bone, and patch clamp studies showing that osteoblasts can fire action potentials (6). The distinct molecular signatures identified suggest a specialization of osteoblast populations that correspond to specific physiological roles such as hormone secretion, bone synthesis, mineralization and neuronal interaction. Reference: (1) Karsenty et al. 2012. Nature 481, 314. (2) Obri et al. 2018. Nat Rev Endocrinol 14, 174. (3) Ducy et al. 1996. Nature 382, 448 (4) Yamamoto et al. 2013. Endocrinology 154, 1008 (5) McDonald et al. 2018. Calcif Tissue Int. 102, 105 (6) Pangalos et al. 2011. J Bioenerg Biomembr 43, 311. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.