Inactivation of beta2-adrenergic signaling improves bone regeneration

Background: The sympathetic nervous system (SNS) represents a critical regulator of skeletal homeostasis, mediated through the release of norepinephrine (NE) in bone.In particular, NE suppresses bone formation and favors bone resorption through beta2-adrenergic receptor signaling (b2AR) in osteoblasts.While the role of b2AR signaling in normal bone turnover is well characterized, its impact on bone regeneration following fracture is unknown.Purpose: To characterize the role of b2AR in bone regeneration.Methods: Male b2AR-deficient mice and littermate controls (FVBN genetic background) were challenged with a femoral osteotomy (Fx), stabilized with an external fixator, at the age of 12 weeks.Radiological and histological analyses of callus architecture were carried out at the early (day 7), intermediate (day 14), and late stages (day 21) of bone regeneration using μCT and BoneJ, respectively.All experiments were approved by the local animal rights protection authorities.Results: Radiologically, no alteration in static callus parameters was observed in b2AR-deficient mice at all time points analyzed (Figure 1).However, Movat Pentachrome staining of non-decalcified callus sections revealed significantly increased mineralized area/ total area on day 7 and 14 and a tendency towards decreased cartilage area/total area (Figure 2).This was accompanied by improved osseous callus bridging in b2AR-deficient mice observed throughout the entire healing process (Figure 3).Conclusions: Together, this study demonstrates an essential role of b2AR in orchestrating callus formation and bone regeneration.As enhanced SNS signaling is critical in trauma, b2AR signaling represents a potential therapeutic target to improve fracture healing in compromised patients.