2019
DOI: 10.1016/j.bone.2019.04.012
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Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice

Abstract: Loss of bone and muscle mass are two major clinical complications among the growing list of chronic diseases that primarily affect elderly individuals. Persistent low-grade inflammation, one of the major drivers of aging, is also associated with both bone and muscle dysfunction in aging. Particularly, chronic activation of the receptor for advanced glycation end products (RAGE) and elevated levels of its ligands high mobility group box 1 (HMGB1), AGEs, S100 proteins and Aβ fibrils have been linked to bone and … Show more

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Cited by 27 publications
(17 citation statements)
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References 78 publications
(109 reference statements)
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“…The underlying pathophysiological mechanisms driving metabolic dysfunction and skeletal fragility in T2D are complex and still need to be better understood, although activation of the RAGE signaling pathway (20) and the accumulation of AGEs in multiple tissues, including bone, have been hypothesized as central mediators (9). Indeed, particularly with prolonged periods of uncontrolled hyperglycemia and during later, more advanced stages of T2D, glucose toxicity contributes to higher levels of AGEs that activate RAGE signaling in various cell types, including those of the osteoblast and myeloid lineages (36,37), contributing to a proinflammatory bone microenvironment that fuels osteoclastogenesis and increased bone resorption (38). This may, at least in part, explain the increased levels of NF-κB (a downstream effector in the RAGE pathway) (20) and RANKL (a protein central to bone resorption because it binds RANK on the surfaces of osteoclast precursors to trigger osteoclastogenesis) (39), which were both detected in bone samples of HFD/ STZ mice.…”
Section: Discussionmentioning
confidence: 99%
“…The underlying pathophysiological mechanisms driving metabolic dysfunction and skeletal fragility in T2D are complex and still need to be better understood, although activation of the RAGE signaling pathway (20) and the accumulation of AGEs in multiple tissues, including bone, have been hypothesized as central mediators (9). Indeed, particularly with prolonged periods of uncontrolled hyperglycemia and during later, more advanced stages of T2D, glucose toxicity contributes to higher levels of AGEs that activate RAGE signaling in various cell types, including those of the osteoblast and myeloid lineages (36,37), contributing to a proinflammatory bone microenvironment that fuels osteoclastogenesis and increased bone resorption (38). This may, at least in part, explain the increased levels of NF-κB (a downstream effector in the RAGE pathway) (20) and RANKL (a protein central to bone resorption because it binds RANK on the surfaces of osteoclast precursors to trigger osteoclastogenesis) (39), which were both detected in bone samples of HFD/ STZ mice.…”
Section: Discussionmentioning
confidence: 99%
“…Bone-derived CM was generated as shown in Davis et al (41). Right femur and tibia from vehicle (V)- and cisplatin (C)-treated mice were carefully cleaned of muscle and fibrous tissues, epiphyses cut, and then marrow-flushed multiple times with αMEM.…”
Section: Methodsmentioning
confidence: 99%
“…Therefore, we speculated that the AGE-RAGE-TXNIP pathway is likely to play an essential role in impairing EPC function by HG. EPCs were treated with BSA-AGE, and the RAGE pathway was blocked by TTP488, a small-molecule inhibitor of RAGE [39]. The results showed that TTP488 inhibited the TXNIP expression, activation of caspase-1, CAT activity damage, hydrogen peroxide accumulation, γ-H2AX, and p21 expression, and restore the expression of Ki67, CD31, and STS had a similar effect to TTP488 (Figure 5F-5H).…”
Section: Sts Improved Cat Activity and Epc Function By Inhibiting The Rage-txnip-caspase-1 Pathwaymentioning
confidence: 82%