Double disruption of α2A- and α2C -adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype

Abstract

Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via b 2 -adrenoceptor (b2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, a 2A -AR and a 2C -AR (a 2A /a 2C -ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In a 2A /a 2C -ARKO versus wild-type (WT) mice, micro-computed tomographic (mCT) analysis showed increased, better connected, and more plate-shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate-resistant acid phosphatase (TRACP) and receptor activator of NF-kB (RANK), which are osteoclast-related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine-regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial b 2 -AR mRNA expression also was similar in KO and WT littermates, whereas a 2A -, a 2B -and a 2C -AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected a 2A -, a 2B -, a 2C -and b 2 -ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5-day-old mouse fetuses and 35-day-old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective a 2 -AR agonist clonidine and to the nonspecific a-AR antagonist phentolamine. These findings suggest that b 2 -AR is not the single adrenoceptor involved in bone turnover regulation and show that a 2 -AR signaling also may mediate the SNS actions in the skeleton. ß

Extracellular Norepinephrine Clearance by the Norepinephrine Transporter Is Required for Skeletal Homeostasis

“…Similarly, reduced sympathetic outflow is observed in patients and rats treated with the NET blockers reboxetine or desipramine (37)(38)(39). On the other hand, ␣ 2A/C AR Ϫ/Ϫ mice have elevated serum NE levels and increased sympathetic outflow associated with a high bone mass (4). The notion that conditions characterized by low sympathetic outflow systematically lead to bone gain is thus not correct.…”

“…The ␤2AR is expressed in both bone mesenchymal and hematopoietic lineages (4 -6). In osteoblasts, its expression is predominant among the nine ␣-and ␤-adrenergic receptor subtypes (␣1A, ␣1B, ␣1D, ␣2A, ␣2B, ␣2C, ␤1, ␤2, and ␤3) (4,7). Moreover, the ␤2AR in osteoblasts is functional, as demonstrated by the accumulation of cAMP and the activation of target genes, including Rankl, upon exogenous stimulation by NE or isoproterenol, a non-selective ␤ adrenergic agonist (1,8).…”

S-nitrosoglutathione reductase–dependent PPARγ denitrosylation participates in MSC-derived adipogenesis and osteogenesis

“…Fat mass, lean mass, and BMD were measured by dualenergy xray absorptiometry (DEXA). μCT was done as described (48). Quantitative histomorphometric analysis was con ducted in a blinded fashion with the OsteoMeasure morphometry system (Osteometrics).…”

Coordination of hypothalamic and pituitary T3 production regulates TSH expression

“…Although it is difficult to speculate on the underlying mechanisms (the global D2 KO has normal BMD; ref. 25), it is known that bone remodeling is under central control via the sympathetic nervous system (30,31), a pathway that is affected by thyroid hormone and D2 expression (32,33). Alternatively, D2 is expressed in bone and mouse osteoblasts (34) as well as in the chicken developing growth plate (35).…”