Mechanical loading alleviated the inhibition of β2‐adrenergic receptor agonist terbutaline on bone regeneration

Abstract

The long-term use of adrenergic medication in treating various conditions, such as asthma, increases the chances of bone fracture. Dynamic mechanical loading at a specific time is a method for improving bone quality and promoting healing.Therefore, we hypothesized that precisely controlling the mechanical environment can contribute to the alleviation of the negative effects of chronic treatment with the common asthma drug terbutaline, which is a β2adrenergic receptor agonist that facilitates bone homeostasis and defect repair through its anabolic effect on osteogenic cells. Our in vitro results showed that terbutaline can directly inhibit osteogenesis by impairing osteogenic differentiation and mineralization. Chronic treatment in vivo was simulated by administering terbutaline to C57BL/6J mice for 4 weeks before bone defect surgery and mechanical loading.We utilized a stabilized tibial defect model, which allowed the application of anabolic mechanical loading. During homeostasis, chronic terbutaline treatment reduced the bone formation rate, the fracture toughness of long bones, and the concentrations of bone formation markers in the sera. During defect repair, terbutaline decreased the bone volume, type H vessel, and total blood vessel volume. Terbutaline treatment reduced the number of osteogenic cells. Periostin, which was secreted mainly by Prrx1+ osteoprogenitors and F4/80+ macrophages, was inhibited by treating the bone defect with terbutaline. Interestingly, controlled mechanical loading facilitated the recovery of bone volume and periostin expression and the number of osteogenic cells within the defect. In conclusion, mechanical loading can rescue negative effects on new bone accrual and repair induced by chronic terbutaline treatment.

Controlled mechanical loading improves bone regeneration by regulating type H vessels in a S1Pr1 ‐dependent manner

“…9 Previous studies have shown mechanical stimulation could increase Type H vessel volume, suggesting that Type H vessels respond to mechanical stimulation. 12,36 is a key regulator in vascularization and sprouting angiogenesis 26,37 and has been shown to be a mechanosensitive protein in vascular ECs. 27,28 However, whether and how S1Pr1 in Type H vessels regulates bone repair is not clear, especially after controlled mechanical loading.…”

“…Type H vessels are unique to the bone, associated with bone modeling and remodeling, and defined by high expression of CD31 and Emcn 9 . Previous studies have shown mechanical stimulation could increase Type H vessel volume, suggesting that Type H vessels respond to mechanical stimulation 12,36 . S1Pr1 is a key regulator in vascularization and sprouting angiogenesis 26,37 and has been shown to be a mechanosensitive protein in vascular ECs 27,28 .…”

Interoceptive regulation of skeletal tissue homeostasis and repair

“…Mechanical loading induces the innervation of sensory and sympathetic neurons inhabiting the skeletal system. Wang et al recently found that mechanical loading significantly reversed β2-AR agonist terbutaline-induced bone loss, 114 suggesting that sympathetic modulation of bone metabolism may be closely associated with the endocrine system or sensory nerve interoception relay. Given these promising findings, further investigation of this regulatory pathway is warranted.…”

Crosstalk between bone and other organs

“…βARs are subdivided into three groups: β1ARs, β2ARs, and β3ARs. Osteoblasts mainly express the β2AR subtype [ 84 , 94 , 95 ]. While β1ARs and β3ARs were found to be weakly expressed or even undetectable in osteoblasts and osteoclasts [ 96 ].…”