Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Area of Science:

• Skeletal biology
• Inflammation research
• Molecular genetics

Background:

• Sharpin is a component of the linear ubiquitin chain assembly complex, regulating NF-κB signaling.
• Inactivating Sharpin mutations in Cpdm mice cause multiorgan inflammation and osteopenia.
• The cellular mechanisms behind Sharpin-deficiency-induced osteopenia were previously undefined.

Purpose of the Study:

• To investigate the cellular mechanisms underlying osteopenia in Cpdm mice.
• To determine the role of Sharpin in bone formation and osteoclastogenesis.
• To explore the molecular response of Cpdm cells to TNF-α.

Main Methods:

• Thorough skeletal phenotyping of Cpdm mice using nondecalcified histology.
• Cellular and dynamic histomorphometry.
• Ex vivo analysis of primary calvarial and CD11b(-) bone marrow cells.
• Genome-wide and gene-specific expression analyses.

Main Results:

• Cpdm mice exhibit trabecular and cortical osteopenia solely due to impaired bone formation; osteoclastogenesis is unaffected.
• Cpdm primary calvarial and bone marrow cells show reduced osteogenic capacity.
• Cpdm mesenchymal cells exhibit increased responsiveness to TNF-α, leading to elevated expression of CXCL5, IL-1β, and IL-6.

Conclusions:

• Skeletal defects in Cpdm mice result from impaired osteoprogenitor cell differentiation.
• Increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype in Sharpin-deficient mice.