Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

Gould, Nicole R.; Williams, Katrina; Joca, Humberto C.; Torre, Olivia M.; Lyons, James S.; Leser, Jenna; Srikanth, Manasa P; Hughes, Marcus; Khairallah, Ramzi J.; Feldman, Ricardo A.; Ward, Christopher W.; Stains, Joseph P.

doi:10.7554/elife.64393

Cited by 24 publications

(27 citation statements)

References 68 publications

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“…8,9 Studies in mice osteocytes and animal models suggest that both transcriptional and posttranscriptional regulation controls sclerostin expression. 10 Rapid changes in sclerostin levels in response to endocrine signals (eg, parathyroid hormone) and mechanical loading may occur as a result of lysosomal degradation of sclerostin protein. 10 These findings illustrate the impact of hormones, biomechanical forces and diet on sclerostin expression in bone and may also influence circulating sclerostin concentrations and expression levels in arteries.…”

Section: Sites and Determinants Of Sclerostin Expressionmentioning

confidence: 99%

Role of Sclerostin in Cardiovascular Disease

Golledge

Thanigaimani

2022

ATVB

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Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin’s role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83–1.57]; P =0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53–1.59]; P =0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.

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Section: Sites and Determinants Of Sclerostin Expressionmentioning

confidence: 99%

Role of Sclerostin in Cardiovascular Disease

Golledge

Thanigaimani

2022

ATVB

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“…Increased ROS levels and osteogenic gene expression in MC3T3-E1 osteoblasts, through MAPK activation mediated by ROS, were described after stimulation by low-intensity pulsed ultrasounds; inhibition of ROS attenuated osteogenic gene expression, including Runx2, osteocalcin, and osteopontin ( Kaur et al, 2017 ). It is also recognized that osteocytes transduce mechanical load signals to activate Nox2, producing ROS signals; this response is accompanied by a rapid ROS-mediated decrease in sclerostin levels by lysosomes, allowing activation of the Wnt/β-catenin signaling pathway, and bone formation ( Schröder, 2015 ; Gould et al, 2021 ). However, in endothelial cells, oxidative stress due to unregulated Nox activity leads to altered eNOS function, shifting from NO production to O 2 − , further inducing oxidative stress and increasing ROS levels, with subsequent endothelial disfunction ( Meza et al, 2019 ).…”

Section: Oxidative Stress and Bone Mechanobiologymentioning

confidence: 99%

In Sickness and in Health: The Oxygen Reactive Species and the Bone

Reis

Ramos

2021

Front. Bioeng. Biotechnol.

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Oxidative stress plays a central role in physiological and pathological bone conditions. Its role in signalment and control of bone cell population differentiation, activity, and fate is increasingly recognized. The possibilities of its use and manipulation with therapeutic goals are virtually unending. However, how redox balance interplays with the response to mechanical stimuli is yet to be fully understood. The present work summarizes current knowledge on these aspects, in an integrative and broad introductory perspective.

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“…Although sclerostin was proven to be a crucial therapeutic target for skeletal diseases, its molecular mechanism of regulation and degradation remains unclear. In addition to transcriptional regulation through the sclerostin gene, a recent report has shown that rapid, minute-scale lysosomal degradation may also be responsible for its down-regulation [ 32 ]. Nevertheless, these results provide strong evidence that the six potential sclerostin-binding inhibitors effectively suppressed the level of both intracellular and extracellular sclerostin.…”

Section: Resultsmentioning

confidence: 99%

Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis

Lee

Hung

et al. 2021

IJMS

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A novel aptamer-based competitive drug screening platform for osteoporosis was devised in which fluorescence-labeled, sclerostin-specific aptamers compete with compounds from selected chemical libraries for the binding of immobilized recombinant human sclerostin to achieve high-throughput screening for potential small-molecule sclerostin inhibitors and to facilitate drug repurposing and drug discovery. Of the 96 selected inhibitors and FDA-approved drugs, six were shown to result in a significant decrease in the fluorescence intensity of the aptamer, suggesting a higher affinity toward sclerostin compared with that of the aptamer. The targets of these potential sclerostin inhibitors were correlated to lipid or bone metabolism, and several of the compounds have already been shown to be potential osteogenic activators, indicating that the aptamer-based competitive drug screening assay offered a potentially reliable strategy for the discovery of target-specific new drugs. The six potential sclerostin inhibitors suppressed the level of both intracellular and/or extracellular sclerostin in mouse osteocyte IDG-SW3 and increased alkaline phosphatase activity in IDG-SW3 cells, human bone marrow-derived mesenchymal stem cells and human fetal osteoblasts hFOB1.19. Potential small-molecule drug candidates obtained in this study are expected to provide new therapeutics for osteoporosis as well as insights into the structure–activity relationship of sclerostin inhibitors for rational drug design.

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Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

Cited by 24 publications

References 68 publications

Role of Sclerostin in Cardiovascular Disease

Role of Sclerostin in Cardiovascular Disease

In Sickness and in Health: The Oxygen Reactive Species and the Bone

Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis

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