Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Oxygen-dependent osteocyte transcriptomic adaptations occur without modulation of endothelial gene expression via osteocyte paracrine signaling

ABSTRACT: Bone regeneration remains clinically challenging, partly due to limited knowledge of the cellular mechanisms governing bone repair. Osteocytes, which constitute the majority of bone cells, form an dendritic network and are central regulators of skeletal homeostasis. Residing in a mineralized and low-oxygen environment, they are exposed to hypoxic conditions that may shape their function, yet the role of hypoxia in osteocyte behavior and angiogenic signaling during bone regeneration is still unclear. This study investigated the effects of hypoxia on osteocytes and their paracrine interaction with endothelial cells. MLO-Y4 osteocytic cells were cultured under normoxia (21% O₂), moderate hypoxia (5% O₂), or severe hypoxia (1% O₂), and conditioned media were applied to mouse endothelial cells. Transcriptomic analyses were performed following optimization of the co-culture model. Hypoxia promoted osteocyte dendritic network development and induced oxygen-dependent metabolic and transcriptional adaptations. Severe hypoxia induces a stronger hypoxic response and glycolytic shift compared with moderate hypoxia, leading to distinct osteocyte profiles. In contrast, osteocyte-conditioned media did not significantly affect endothelial gene expression, suggesting that hypoxia-independent mechanisms may govern osteocyte-endothelial communication. These findings highlight oxygen availability as a key regulator of osteocyte physiology and underscore the need for further investigation into its role during bone regeneration.

INSTRUMENT(S): NextSeq 2000

ORGANISM(S): Mus musculus

SUBMITTER: Frédéric Martins

PROVIDER: E-MTAB-16618 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Osteogenesis imperfecta (OI) is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility. While these disorders have traditionally been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes, descendants of osteoblasts, in OI pathogenesis remains unknown. The homozygous human SP7 (c.946C > T, R316C) mutation results in a recessive form of osteogenesis imperfecta characterized by short stature, fragility fractures, low bone mineral density, and osteocyte dendrite defects. To better understand how the osteogenesis imperfecta-causingSP7 R316Cmutation affects the function of this transcription factor in different osteoblast lineage cells in bone, we generatedSp7 R342Cknock-in mice. Homozygous mutantSp7 R342C/R342Cmice demonstrate increased cortical porosity and reduced cortical bone mineral density, findings consistent with phenotypes observed in patients with this mutation. Sp7 R342Cmice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling characterized by ectopic intracortical osteoclasts and elevated Tnfsf11 expression by osteocytes. Remarkably, these overt defects in osteocyte function contrast to preserved osteoblast function, suggesting that this Sp7 point mutation selectively interferes with the function of this transcription factor in osteocytes but not osteoblasts. Osteocyte morphology changes in Sp7 R342C/R342Cmice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intra-cortical osteoclast activity in this model. Moreover, transcriptomic profiling reveals that the expression of a core set osteocyte-enriched genes is highly dysregulated by the R342C mutation. Thus, this model supports a model in which osteocyte dysfunction can drive osteogenesis imperfecta pathogenesis, and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone homeostasis and remodeling.

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Oxygen-dependent osteocyte transcriptomic adaptations occur without modulation of endothelial gene expression via osteocyte paracrine signaling

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