Osteocytes regulate senescence of bone and bone marrow.

Area of Science:

• Skeletal Biology
• Cellular Homeostasis
• Immunology

Background:

• The skeletal system relies on mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) for bone and bone marrow homeostasis.
• Osteocytes, embedded within the bone matrix, are increasingly recognized for their regulatory roles.

Purpose of the Study:

• To investigate the role of osteocytes in regulating skeletal and bone marrow cellular lineages and tissue homeostasis.
• To determine the consequences of osteocyte ablation on organismal health and cellular differentiation.

Main Methods:

• Utilized a mouse model with conditional deletion of dentin matrix protein 1 (DMP1)-positive osteocytes using diphtheria toxin subunit α.
• Performed single-cell RNA sequencing to analyze cellular lineage alterations.
• Assessed skeletal phenotypes, lifespan, and cellular senescence markers.

Main Results:

• Partial ablation of osteocytes resulted in sarcopenia, osteoporosis, kyphosis, and reduced lifespan.
• Osteocyte reduction impaired osteogenesis and promoted osteoclastogenesis, altering mesenchymal lineage commitment.
• Hematopoietic stem cell differentiation shifted towards myeloid lineages (neutrophils, monocytes) with impaired lymphopoiesis (reduced B cells).
• Cellular senescence, specifically the senescence-associated secretory phenotype (SASP), was identified as a key mechanism.

Conclusions:

• Osteocytes are critical regulators of mesenchymal and hematopoietic lineage cell specification in bone and bone marrow.
• Osteocyte dysfunction contributes to skeletal degeneration and immune dysregulation through senescence pathways.
• Targeting osteocyte-mediated senescence may offer therapeutic strategies for bone and immune disorders.