Agrin Ablation in Osteoblasts Compromises Long Bone Structure and Osteoblastic Differentiation of Mesenchymal Stem...

Agrin is an important factor in maintaining skeletal architecture. However, the role of osteoblast-expressed agrin in bone tissue remains unexplored. Thus, we hypothesized that agrin-deficient osteoblasts negatively affect bone tissue homeostasis by disrupting osteoblastic differentiation of mesenchymal stem cells (MSCs). To investigate this hypothesis, mice with deletion of agrin in Runx2-expressing osteoblasts were generated using Runx2-Cre mice. Microtomographic analyses revealed that agrin ablation in osteoblasts resulted in deleterious effects on the cortical bone of the femurs, leading to a tendency towards reduced bone stiffness, as indicated by the three-point bending test. This negative impact of agrin-deficient osteoblasts on bone tissue may be partially attributed to the reduced osteoblastic differentiation of MSCs derived from these mice, as evidenced by lower expression of osteoblastic marker genes and alkaline phosphatase activity. This disruption in osteoblastic differentiation is directly linked to agrin-deficient osteoblasts, as demonstrated by diminished gene expression of agrin and its receptors in MSCs collected from these animals. Our findings highlight the role of osteoblast-secreted agrin in maintaining long bone structure, mainly by promoting MSC differentiation into osteoblasts. The findings indicate that agrin could be an effective therapeutic target for treating bone loss-related conditions, such as osteoporosis and aging.