β2-adrenoceptor signaling in chondrocytes regulates long bone growth, bone homeostasis, and fracture healing in mice.

Catecholamines are known to interact with bone and cartilage cells via binding to adrenergic receptors. Among these, the β2-adrenoceptor (β2-AR) plays a key role in mediating the effects of catecholamines on bone. Mice lacking the β2-AR systemically or specifically in osteoblasts show an increased bone mass. Previous studies further indicated an important influence of catecholamines on transdifferentiation of chondrocytes towards osteoblasts during endochondral ossification. Therefore, in this study, cartilage and bone phenotype as well as fracture healing of mice with a specific knockout of the β2-AR in chondrocytes were investigated. Tibiae and femora of 6-, 12-, and 40-wk-old male and female mice were analyzed. The knockout resulted in a reduced long bone growth, most likely due to a faster transition of proliferative to hypertrophic chondrocytes. The older knockout mice additionally showed an osteopenic bone phenotype due to a reduced number of osteoblasts. Fracture healing after a standardized femur osteotomy was delayed, showing reduced cartilage area at an intermediate time point during fracture healing. Gene expression analysis in an additional in-vitro-experiment identified pathways like "Wnt-signaling" and "TGFβ-signaling" to be involved. In conclusion, our data showed an important role of the β2-AR specifically in chondrocytes during long bone growth, bone homeostasis in older animals and fracture healing.