Cyclooxygenase 2 augments osteoblastic but suppresses chondrocytic differentiation of CD90⁺ skeletal stem cells in fracture sites

Cyclooxygenase 2 (COX-2) is essential for normal tissue repair. Although COX-2 is known to enhance the differentiation of mesenchymal stem cells (MSCs), how COX-2 regulates MSC differentiation into different tissue-specific progenitors to promote tissue repair remains unknown. Because it has been shown that COX-2 is critical for normal bone repair and local COX-2 overexpression in fracture sites accelerates fracture repair, this study aimed to determine the MSC subsets that are targeted by COX-2. We showed that CD90⁺ mouse skeletal stem cells (mSSCs; i.e., CD45⁻Tie2⁻AlphaV⁺ MSCs) were selectively recruited by macrophage/monocyte chemoattractant protein 1 into fracture sites following local COX-2 overexpression. In addition, local COX-2 overexpression augmented osteoblast differentiation and suppressed chondrocyte differentiation in CD90⁺ mSSCs, which depended on canonical WNT signaling. CD90 depletion data demonstrated that local COX-2 overexpression targeted CD90⁺ mSSCs to accelerate fracture repair. In conclusion, CD90⁺ mSSCs are promising targets for the acceleration of bone repair.