Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Jialiang S. Wang, Tushar Kamath, Courtney M. Mazur, Fatemeh Mirzamohammadi, Daniel Rotter, Hironori Hojo, Christian D. Castro, Nicha Tokavanich, Rushi Patel, Nicolas Govea, Tetsuya Enishi, Yunshu Wu, Janaina Silva Martins, Michael Bruce, Daniel J. Brooks, Mary L. Bouxsein, Danielle Tokarz, Charles P. Lin, Abdul Abdul, Evan Z. Macosko, Melissa Fiscaletti, Craig F. Munns, Pearl Ryder, Maria Kost-Alimova, Patrick Byrne, Beth Cimini, Makoto Fujiwara, Henry M. Kronenberg and Marc N. Wein ()
Additional contact information
Jialiang S. Wang: Harvard Medical School
Tushar Kamath: Broad Institute of Harvard and MIT
Courtney M. Mazur: Harvard Medical School
Fatemeh Mirzamohammadi: Harvard Medical School
Daniel Rotter: Harvard Medical School
Hironori Hojo: The University of Tokyo Graduate School of Medicine
Christian D. Castro: Harvard Medical School
Nicha Tokavanich: Harvard Medical School
Rushi Patel: Harvard Medical School
Nicolas Govea: Harvard Medical School
Tetsuya Enishi: Harvard Medical School
Yunshu Wu: Harvard Medical School
Janaina Silva Martins: Harvard Medical School
Michael Bruce: Harvard Medical School
Daniel J. Brooks: Harvard Medical School
Mary L. Bouxsein: Harvard Medical School
Danielle Tokarz: Harvard Medical School
Charles P. Lin: Harvard Medical School
Abdul Abdul: Broad Institute of Harvard and MIT
Evan Z. Macosko: Broad Institute of Harvard and MIT
Melissa Fiscaletti: Sainte-Justine University Hospital Centre
Craig F. Munns: The Children’s Hospital at Westmead
Pearl Ryder: Broad Institute of Harvard and MIT
Maria Kost-Alimova: Broad Institute of Harvard and MIT
Patrick Byrne: Broad Institute of Harvard and MIT
Beth Cimini: Broad Institute of Harvard and MIT
Makoto Fujiwara: Osaka University Graduate School of Medicine
Henry M. Kronenberg: Harvard Medical School
Marc N. Wein: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during “osteocytogenesis” is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.

Date: 2021
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DOI: 10.1038/s41467-021-26571-7

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