Biased and allosteric modulation of bone cell-expressing G protein-coupled receptors as a novel approach to osteoporosis therapy

Kalinkovich, Alexander; Livshits, Gregory

doi:10.1016/j.phrs.2021.105794

Cited by 19 publications

(6 citation statements)

References 235 publications

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“…Aging in both animals and humans is positively correlated with a decline in the physiological functions, thereby increasing the occurrence of aging-related diseases; such as neurodegenerative diseases (NDS) (1) including Alzheimer's disease (AD) (2), Parkinson's disease (PD) (3), Huntington's disease (HD) (4), and Depression (5); as well as other related diseases such as Osteoporosis (6), Myocardial ischemia (M/I) and reperfusion (MI/R) (7), Atherosclerosis (AS) (8), and Diabetes (9). A study reported that agingrelated NDS caused significant morbidity and economic burden of approximately $25 billion annually in the USA (10).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

et al. 2022

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Quercetin, a naturally non-toxic flavonoid within the safe dose range with antioxidant, anti-apoptotic and anti-inflammatory properties, plays an important role in the treatment of aging-related diseases. Sirtuin 1 (SIRT1), a member of NAD+-dependent deacetylase enzyme family, is extensively explored as a potential therapeutic target for attenuating aging-induced disorders. SIRT1 possess beneficial effects against aging-related diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Depression, Osteoporosis, Myocardial ischemia (M/I) and reperfusion (MI/R), Atherosclerosis (AS), and Diabetes. Previous studies have reported that aging increases tissue susceptibility, whereas, SIRT1 regulates cellular senescence and multiple aging-related cellular processes, including SIRT1/Keap1/Nrf2/HO-1 and SIRTI/PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB and SIRT1/NLRP3 regulated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP and SIRT1/PKD1/CREB controlled phosphorylation, SIRT1-PINK1-Parkin mediated mitochondrial damage, SIRT1/FoxO mediated autophagy, and SIRT1/FoxG1/CREB/BDNF/Trkβ-catenin mediated neuroprotective effects. In this review, we summarized the role of SIRT1 in the improvement of the attenuation effect of quercetin on aging-related diseases and the relationship between relevant signaling pathways regulated by SIRT1. Moreover, the functional regulation of quercetin in aging-related markers such as oxidative stress, inflammatory response, mitochondrial function, autophagy and apoptosis through SIRT1 was discussed. Finally, the prospects of an extracellular vesicles (EVs) as quercetin loading and delivery, and SIRT1-mediated EVs as signal carriers for treating aging-related diseases, as well as discussed the ferroptosis alleviation effects of quercetin to protect against aging-related disease via activating SIRT1. Generally, SIRT1 may serve as a promising therapeutic target in the treatment of aging-related diseases via inhibiting oxidative stress, reducing inflammatory responses, and restoring mitochondrial dysfunction.

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Section: Introductionmentioning

confidence: 99%

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

et al. 2022

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“…It is clear, now, that the agonist-induced receptor response is influenced by its immediate surroundings, at the membrane levels, including (i) the presence of other receptors that might heterodimerize with the target, (ii) the presence of G proteins and the absence of other ones, leading, already, to some sources of bias, (iii) the very existence of endogenous modulator(s)-proteins or small molecules-that could be positive or negative modulators at this and (iv) the difficult question of the relative concentrations of each previously mentioned actor of the receptor biochemistry (Figure 3). Despite these complexities, the dimension of biaism has started to be integrated into the therapeutical research, such as in osteoporosis therapy [79] or in neurological disease therapies [80], among others. As a conclusive remark, we would like to insist on the following two aspects of the present commentary: (i) it is not meant to be extensive, as an in-depth review on the subject can be and (ii) we found the landscape extremely complex, as might be predicted for living systems which have evolved for several million years, due to our tunnel vision of GPCR biology, biochemistry and pharmacology.…”

Section: Context Of Complexity In Receptologymentioning

confidence: 99%

Biased Agonism or “Biaism” for Dummies: A Commentary

Boutin,

Leprince

2024

Receptors

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That signaling bias is a nth level of complexity in the understanding of G protein-coupled receptor (GPCR) activation is a first fact. That its exhaustive description, including the mode d’emploi of its quantitative measurement, remains a challenge is a second fact. That the use of this concept is promising for the design of drug candidates is a third fact. That the translation of signaling biases observed into in vivo specific effects is well documented is a fourth fact. However, the road to apply those aspects of receptology to a systematic description of a ligand and, a fortiori, of a drug candidate, still necessitates a huge body of studies. In the present commentary, the merits of the molecular description of receptor bias signaling are highlighted and the ligand induced-fit impact on GPCR structure, as well as on the functional repertoire of GPCRs, is discussed. An emphasis is given to the practical aspects during drug design, and, thus, the practical limitations of the current approaches, particularly in the context of as soon as the data are transferred to more integrated/living systems, might be a major limitation.

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“…During bone formation, bone marrow mesenchymal stem cells (BMSCs) differentiate into osteoblasts (OBs), which secrete collagen fibers and bone matrix, gradually accumulate calcium, and form bones ( Mizoguchi and Ono, 2021 ); whereas during bone resorption, osteoclasts (OCs) dissolve and resorb the old bone formed via necrotic and apoptotic osteocytes ( Da et al, 2021 ). The interaction between OBs and OCs maintains a normal healthy bone mass ( Long, 2011 ; Croucher et al, 2016 ; Kalinkovich and Livshits, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…maintains a normal healthy bone mass (Long, 2011;Croucher et al, 2016;Kalinkovich and Livshits, 2021).…”

mentioning

confidence: 99%

Role of SIRT3 in bone homeostasis and its application in preventing and treating bone diseases

Xu,

Li,

Wen

et al. 2023

Front. Pharmacol.

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Bone homeostasis refers to the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption and the maintenance of stable bone mass. SIRT3 is a class of mitochondrial protein deacetylase that influences various mitochondrial functions and is involved in the mechanisms underlying resistance to aging; regulation of bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts; and development of osteoporosis, osteoarthritis, and other bone diseases. Moreover, exercise affects bones through SIRT3. Thus, studies on SIRT3 may provide insights for the treatment of bone diseases. Although SIRT3 can exert multiple effects on bone, the specific mechanism by which it regulates bone homeostasis remains unclear. By evaluating the relevant literature, this review discusses the structure and function of SIRT3, reveals the role and associated mechanisms of SIRT3 in regulating bone homeostasis and mediating bone health during exercise, and highlights the potential pharmacological value of SIRT3 in treating bone diseases.

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Biased and allosteric modulation of bone cell-expressing G protein-coupled receptors as a novel approach to osteoporosis therapy

Cited by 19 publications

References 235 publications

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

Biased Agonism or “Biaism” for Dummies: A Commentary

Role of SIRT3 in bone homeostasis and its application in preventing and treating bone diseases

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