gms | German Medical Science

Objectives: Impaired bone healing is a major public health concern due to the increasing number of age-related fractures. Previous evidence has shown that the sympathetic nervous system inhibits bone formation and promotes bone resorption through the G protein-coupled beta2-adrenergic receptor (Adrb2) in 24-week-old mice, which have a physiologically elevated sympathetic tone at this age. Here, genetic or pharmacological inhibition of Adrb2 signaling resulted in high bone mass, identifying this cell surface receptor as a potential target for the treatment of bone loss disorders. However, the role of Adrb2 in bone regeneration after fracture remains largely unknown. This study was therefore designed to characterize the role of Adrb2 in fracture healing in young and adult mice.

Methods: For genetic experiments, Adrb2-deficient mice and littermate controls received a femoral osteotomy, stabilized with an external fixator (Fx) at 12 (young) or 30 (adult) weeks of age. For pharmacological experiments, adult wildtype Fx mice were treated daily with either the non-specific Adrb2 antagonist propranolol or the Adrb2-specific agonist formoterol, starting on the day of surgery. An additional set of wildtype mice received the beta1-adrenergic (Adrb1) antagonist atenolol as control. In all experiments, analyses of callus architecture were carried out at the early (day 7), intermediate (day 14), and late stages (day 21) of bone regeneration using micro-CT and histomorphometry of callus cryo-sections stained with Movat-Pentachrome. Furthermore, non-decalcified histology and radiological analysis were used to assess bone remodeling in the spine and femur of uninjured Adrb2-deficient and littermate controls.

Results and conclusion: Young Adrb2-deficient mice with low sympathetic tone showed normal bone architecture in the unfractured skeleton and only minor alterations in bone regeneration. However, adult Adrb2-deficient mice with elevated sympathetic activity showed increased trabecular bone mass in the spine and femur as described previously. In sharp contrast, callus mineralization and maturation were severely impaired and characterized by atrophic nonunion with reduced cellular callus remodeling in mutant mice at this age. Pharmacologically, the non-specific beta-blocker propranolol impaired fracture healing, whereas the Adrb2 agonist formoterol accelerated bone repair in adult wildtype mice and atenolol had no effect. Together, Adrb2 plays a critical role in bone regeneration in adult mice and can be targeted pharmacologically to promote fracture healing. Clinical studies are now needed to delineate the impact of the relative roles of Adrb1 and Adrb2 signaling in bone regeneration in humans.

Figure 1 [Fig. 1]