Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and...

Area of Science:

• Regenerative Medicine
• Stem Cell Biology
• Skeletal Biology

Background:

• Muscle-derived stem cells (MDSCs) show promise for bone regeneration.
• The role of cyclooxygenase-2 (COX-2) in MDSC-mediated bone repair is not fully understood.

Purpose of the Study:

• To investigate the impact of COX-2 expression in donor and host cells on MDSC-driven bone regeneration.
• To elucidate the mechanisms underlying impaired bone formation in the absence of COX-2.

Main Methods:

• Utilized a critical size calvarial defect model in mice.
• Employed COX-2 knock-out (Cox-2KO) and wild-type (WT) mice and MDSCs.
• Transplanted BMP4/green fluorescent protein (GFP)-transduced MDSCs.
• Analyzed bone formation, cellular signaling (BMP4-pSMAD1/5), osteogenic differentiation, proliferation, survival, and macrophage recruitment.

Main Results:

• Cox-2KO MDSCs formed significantly less bone than WT MDSCs in both Cox-2KO and WT host mice.
• Impaired bone regeneration was linked to downregulated BMP4-pSMAD1/5 signaling, reduced osteogenic differentiation, and lower proliferation capacity.
• Cox-2KO MDSCs exhibited decreased cell survival and osteogenic differentiation in vitro, partly due to Igf1 and Igf2 downregulation.
• Cox-2KO MDSCs recruited fewer macrophages early after injury.

Conclusions:

• COX-2 expression is essential for optimal MDSC-mediated bone regeneration.
• COX-2 deficiency in MDSCs compromises bone formation by reducing cell proliferation, survival, osteogenic differentiation, and host cell recruitment.
• Targeting COX-2 may enhance the efficacy of stem cell therapies for bone repair.