Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption

Ariza, Yuko; Murata, Masayuki; Ueda, Yoshiko; Yoshizawa, Toshio

doi:10.1016/j.bonr.2019.100201

Cited by 19 publications

(22 citation statements)

References 33 publications

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“…Surprisingly, we found a significant decrease in BMD in male, but not female mice, 48 hr after two consecutive systemic RANKL injections. Previous work shows osteoclast activation in both male and female mice (Ariza et al, 2019;Ding et al, 2020;Li et al, 2015;Shin et al, 2014;Tomimori et al, 2009). One possibility for the discrepancy between our data and other studies may be related to a reduction in the accuracy of trabecular BMDs below 250 mg/cm 3 when using two phantoms of calcium-hydroxyapatite of 250 and 750 mg/ cm 3 to estimate density.…”

Section: Rankl-induced Bone Resorptioncontrasting

confidence: 98%

Physiologic osteoclasts are not sufficient to induce skeletal pain in mice

Clauser

Santana-Varela

Wood

et al. 2020

European Journal of Pain

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Background: Increased bone resorption is driven by augmented osteoclast activity in pathological states of the bone, including osteoporosis, fracture and metastatic bone cancer. Pain is a frequent co-morbidity in bone pathologies and adequate pain management is necessary for symptomatic relief. Bone cancer is associated with severe skeletal pain and dysregulated bone remodelling, while increased osteoclast activity and bone pain are also observed in osteoporosis and during fracture repair. However, the effects of altered osteoclast activity and bone resorption on nociceptive processing of bone afferents remain unclear. Methods: This study investigates whether physiologic osteoclasts and resulting changes in bone resorption can induce skeletal pain. We first assessed correlation between changes in bone microarchitecture (through µCT) and skeletal pain using standardized behavioural phenotyping assays in a mouse model of metastatic bone cancer. We then investigated whether increased activity of physiologic osteoclasts, and the associated bone resorption, is sufficient to induce skeletal pain using mouse models of localized and widespread bone resorption following administration of exogenous receptor activator of nuclear factor kappa-B ligand (RANKL). Results: Our data demonstrates that mice with bone cancer exhibit progressive pain behaviours that correlate with increased bone resorption at the tumour site. Systemic RANKL injections enhance osteoclast activity and associated bone resorption, without producing any changes in motor function or pain behaviours at both early and late timepoints. Conclusion: These findings suggest that activation of homeostatic osteoclasts alone is not sufficient to induce skeletal pain in mice. Significance statement: The role of osteoclasts in peripheral sensitization of sensory neurones is not fully understood. This study reports on the direct link between oestrogen-independent osteoclast activation and skeletal pain. Administration of exogenous receptor activator of nuclear factor kappa-B ligand (RANKL) increases bone resorption, but does not produce pro-nociceptive changes in behavioural pain thresholds. Our data demonstrates that physiologic osteoclasts are not essential for skeletal pain behaviours. This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Rankl-induced Bone Resorptioncontrasting

confidence: 98%

Physiologic osteoclasts are not sufficient to induce skeletal pain in mice

Clauser

Santana-Varela

Wood

et al. 2020

European Journal of Pain

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“…BTK links RANK (receptor activator of NF-κΒ) activation together with co-stimulation, for example by FcRs, to drive osteoclast differentiation [76]. This can play a pathogenic role in systemic autoimmune diseases such as RA [76,77]. BTK is involved in downstream signaling of several chemokine receptors, including CXCR4 [78], and in the intracellular signal transduction required for integrin activation and upregulation [79][80][81].…”

Section: Btk In Other Signaling Pathwaysmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Neys

Rip

Hendriks

et al. 2021

Drugs

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Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by “classical” anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated. Bruton’s tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival. BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity. This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases. The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects. The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients. In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials.

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“… 18 Prominent and more selective second-generation irreversible inhibitors of BTK include tirabrutinib (ONO/GS-4059), a dual BTK and Tec inhibitor currently in Phase I clinical trials for RA, as well as spebrutinib (CC-292, AVL-292), acalabrutinib (ACP-196), and evobrutinib (M-2951), all of which are actively undergoing Phase II RA trials. 15 , 19 , 20 Evobrutinib is notable for its high potency in inhibiting both BCR and Fc receptor signaling, strongly favoring BTK as a target over similar kinases in the Tec family. 21–23 Poseltinib (previously LY3337641/HM71224) is a selective irreversible BTK inhibitor that completed a phase I trial in RA, leading to a phase II trial that was aborted due to low likelihood of achieving adequate clinical response in interim analysis.…”

Section: Btk Inhibitors In Developmentmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibition for the Treatment of Rheumatoid Arthritis

Arneson¹,

Carroll²,

Ruderman³

2021

ITT

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Bruton’s tyrosine kinase (BTK) inhibitors are an emerging class of drugs that inhibit B cell receptor activation, FC-γ receptor signaling, and osteoclast proliferation. Following on approval for treatment of hematologic malignancies, BTK inhibitors are now under investigation to treat a number of different autoimmune diseases, including rheumatoid arthritis (RA). While the results of BTK inhibitors in RA animal models have been promising, the ensuing human clinical trial outcomes have been rather equivocal. This review will outline the mechanisms of BTK inhibition and its potential impact on immune mediated disease, the types of BTK inhibitors being studied for RA, the findings from both preclinical and clinical trials of BTK inhibitors in RA, and directions for future research.

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Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption

Cited by 19 publications

References 33 publications

Physiologic osteoclasts are not sufficient to induce skeletal pain in mice

Physiologic osteoclasts are not sufficient to induce skeletal pain in mice

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Bruton’s Tyrosine Kinase Inhibition for the Treatment of Rheumatoid Arthritis

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