Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice

Davis, Hannah M.; Essex, Alyson L.; Valdez, Sinai; Deosthale, Padmini; Aref, Mohammad W.; Allen, Matthew R.; Bonetto, Andrea; Plotkin, Lilian I.

doi:10.1016/j.bone.2019.04.012

Cited by 28 publications

(24 citation statements)

References 78 publications

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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%

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

Eckhardt¹,

Rowsey²,

Thicke³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

Eckhardt¹,

Rowsey²,

Thicke³

et al. 2020

JCI Insight

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“…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%

Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice

Essex

Huot

et al. 2019

Front. Endocrinol.

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Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mechanisms also take place following treatments with anticancer drugs. In this study, we found that young male CD2F1 mice (8-week old) treated with the chemotherapeutic agent cisplatin (2.5 mg/kg) presented marked loss of muscle and bone mass. Myotubes exposed to bone conditioned medium from cisplatin-treated mice showed severe atrophy (−33%) suggesting a bone to muscle crosstalk. To test this hypothesis, mice were administered cisplatin in combination with an antiresorptive drug to determine if preservation of bone mass has an effect on muscle mass and strength following chemotherapy treatment. Mice received cisplatin alone or combined with zoledronic acid (ZA; 5 μg/kg), a bisphosphonate routinely used for the treatment of osteoporosis. We found that cisplatin resulted in progressive loss of body weight (−25%), in line with reduced fat (−58%) and lean (−17%) mass. As expected, microCT bone histomorphometry analysis revealed significant reduction in bone mass following administration of chemotherapy, in line with reduced trabecular bone volume (BV/TV) and number (Tb.N), as well as increased trabecular separation (Tb.Sp) in the distal femur. Conversely, trabecular bone was protected when cisplatin was administered in combination with ZA. Interestingly, while the animals exposed to chemotherapy presented significant muscle wasting (~-20% vs. vehicle-treated mice), the administration of ZA in combination with cisplatin resulted in preservation of muscle mass (+12%) and strength (+42%). Altogether, these observations support our hypothesis of bone factors targeting muscle and suggest that pharmacological preservation of bone mass can benefit muscle mass and function following chemotherapy.

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“…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%

STS Protects Diabetic Glomerular Vascular Endothelial Barrier by Ameliorating EPC Dysfunction: Targeting RAGE-TXNIP-NLRP3 Inflammasome Pathway

Heng

Zhang

Wang

et al. 2021

Preprint

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Background: Glomerular endothelial cell (GEC) injury is one of the crucial causes of diabetic kidney disease (DKD). Endothelial progenitor cell (EPC) is the essential mechanism of vascular endothelial repair, which damages by diabetic pathology. Sodium Tanshinone Sulfonate ⅡA (STS) is known to protect endothelium, but the mechanism and the role in DKD need to be studied. Methods: EPC was treated with high glucose (HG), and thioredoxin interacting protein (TXNIP), NLR family pyrin domain containing 3 (NLRP3) inflammasome, DNA damage, proliferation, differentiation and senescence were detected; STS and EPC were intravenous injected into diabetic nude mice, the urine protein quantitation and urine protein/creatinine were detected; the Dil-labeled EPC was traced and the expression of TXNIP, caspase-1 (p20), p21, Ki67, CD31 were detected by fluorescence co-location in glomerulus.Results: We found that STS inhibited HG-induced TXNIP expression and NLRP3 inflammasome activation, catalase (CAT) inactivation, DNA damage, senescence； STS restored EPC proliferation and differentiation functions; advanced glycation end products (AGEs) produced in HG treated EPC supernatant, the receptor of AGE (RAGE) blocking inhibited TXNIP expression and NLRP3 inflammasome activation, which mimicked by STS. STS protected EPC functions in diabetic glomerular and enhanced EPC renal function amelioration. Conclusions: We concluded that STS watched CAT activity to prevent HG-induced EPC DNA damage, proliferation, differentiation dysfunction, accelerated senescence by inhibiting the RAGE-TXNIP-NLRP3 inflammasome-caspase-1 pathway.

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Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice

Cited by 28 publications

References 78 publications

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice

STS Protects Diabetic Glomerular Vascular Endothelial Barrier by Ameliorating EPC Dysfunction: Targeting RAGE-TXNIP-NLRP3 Inflammasome Pathway

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