MiR-1 is a critical regulator of chondrocyte proliferation and hypertrophy by inhibiting Indian hedgehog pathway during postnatal endochondral ossification in miR-1 overexpression transgenic mice.

Abstract

Endochondral bone formation from the growth plate plays a critical role in vertebrate limb development and skeletal homeostasis. Although miR-1 is mainly expressed in the hypertrophic region of the growth plate during this process, its role in the endochondral bone formation is unknown. To elucidate the role of miR-1 in cartilage development, chondrocyte-specific transgenic mice with high expression of miR-1 were generated (Col2a1-Cre-ERT2-GFPfl/fl-RFP-miR-1). Transgenic mice showed short limbs and delayed formation of secondary ossification centers. In the tibia growth plate of miR-1-overexpressing transgenic mice, the chondrocytes in the proliferative zone were disorganized and their proliferation decreased, and the ColX, MMP-13 and Indian Hedgehog (IHH) in chondrocytes showed a downward trend, resulting in decreased terminal differentiation in the hypertrophic zone. In addition, the apoptosis index caspase-3 also showed a downward trend in the tibia growth plate. It was concluded that miR-1 overexpression affects chondrocyte proliferation, hypertrophic differentiation, and apoptosis, thereby delaying the formation of secondary ossification centers and leading to short limbs. It was also verified that miR-1 affects endochondral ossification through the IHH pathway. The above results suggest that miR-1 overexpression can affect endochondral osteogenesis by inhibiting chondrocyte proliferation, hypertrophic differentiation, and apoptosis, thus causing limb hypoplasia in mice. This work gives potential for new therapeutic directions and insights for the treatment of dwarf-related diseases.