Novel cathepsin K inhibitors block osteoclasts <i>in vitro</i> and increase spinal bone density in zebrafish

Xue, Si-tu; Wang, Yali; Han, Xiao-wan; Yang, Hong; Jiang, Wei; Si, Shuyi; Guo, Han; Li, Zhuorong

doi:10.1039/c8ra10338k

Cited by 6 publications

(5 citation statements)

References 40 publications

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“…In recent years, CTSK inhibitors have been developed by pharmaceutical companies as potential anti-resorptive agents ( Dai et al, 2020 ). The pharmacological effects of CTSK inhibitors on osteoporosis have been demonstrated in zebrafish, rodent models, and humans ( Stoch and Wagner, 2008 ; Xue et al, 2019 ). In this study, the cell-free CTSK enzymatic assay revealed that 10-gingerol possessed CTSK inhibition ability ( Figure 4H ).…”

Section: Discussionmentioning

confidence: 99%

10-Gingerol Suppresses Osteoclastogenesis in RAW264.7 Cells and Zebrafish Osteoporotic Scales

Zang

Kagotani

Nakayama

et al. 2021

Front. Cell Dev. Biol.

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Osteoporosis is the most common aging-associated bone disease and is caused by hyperactivation of osteoclastic activity. We previously reported that the hexane extract of ginger rhizome [ginger hexane extract (GHE)] could suppress receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in RAW264.7 cells. However, the anti-osteoclastic components in GHE have not yet been identified. In this study, we separated GHE into several fractions using silica gel column chromatography and evaluated their effects on osteoclastogenesis using a RAW264.7 cell osteoclast differentiation assay (in vitro) and the zebrafish scale model of osteoporosis (in vivo). We identified that the fractions containing 10-gingerol suppressed osteoclastogenesis in RAW264.7 cells detected by tartrate-resistant acid phosphatase (TRAP) staining. In zebrafish, GHE and 10-gingerol suppressed osteoclastogenesis in prednisolone-induced osteoporosis regenerated scales to promote normal regeneration. Gene expression analysis revealed that 10-gingerol suppressed osteoclast markers in RAW264.7 cells [osteoclast-associated immunoglobulin-like receptor, dendrocyte-expressed seven transmembrane protein, and matrix metallopeptidase-9 (Mmp9)] and zebrafish scales [osteoclast-specific cathepsin K (CTSK), mmp2, and mmp9]. Interestingly, nuclear factor of activated T-cells cytoplasmic 1, a master transcription regulator of osteoclast differentiation upstream of the osteoclastic activators, was downregulated in zebrafish scales but showed no alteration in RAW264.7 cells. In addition, 10-gingerol inhibited CTSK activity under cell-free conditions. This is the first study, to our knowledge, that has found that 10-gingerol in GHE could suppress osteoclastic activity in both in vitro and in vivo conditions.

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Section: Discussionmentioning

confidence: 99%

10-Gingerol Suppresses Osteoclastogenesis in RAW264.7 Cells and Zebrafish Osteoporotic Scales

Zang

Kagotani

Nakayama

et al. 2021

Front. Cell Dev. Biol.

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“…CTSK is secreted from the lysosomes of mature osteoclasts and interacts with the E3 ubiquitin ligase Cb1 (Tyr737) adaptor protein and the PI3K p85 regulatory subunit [ 75 ]. A22, a specific potent inhibitor of CTSK, blocked osteoclast activation in vitro and enhanced the spine bone density in zebrafish [ 76 ]. In clinical tests, a series of pharmaceutical products were applied to inhibit CTSK activity, such as balicatib (AAE581), ONO-5534, and odanacatib, which were mostly efficacious for inhibiting osteoclast bone resorption and preventing bone loss.…”

Section: Master Regulators Of Osteoclastogenesismentioning

confidence: 99%

A Review of Signaling Transduction Mechanisms in Osteoclastogenesis Regulation by Autophagy, Inflammation, and Immunity

Tong

Guo

et al. 2022

IJMS

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Osteoclastogenesis is an ongoing rigorous course that includes osteoclast precursors fusion and bone resorption executed by degradative enzymes. Osteoclastogenesis is controlled by endogenous signaling and/or regulators or affected by exogenous conditions and can also be controlled both internally and externally. More evidence indicates that autophagy, inflammation, and immunity are closely related to osteoclastogenesis and involve multiple intracellular organelles (e.g., lysosomes and autophagosomes) and certain inflammatory or immunological factors. Based on the literature on osteoclastogenesis induced by different regulatory aspects, emerging basic cross-studies have reported the emerging disquisitive orientation for osteoclast differentiation and function. In this review, we summarize the partial potential therapeutic targets for osteoclast differentiation and function, including the signaling pathways and various cellular processes.

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“…Meanwhile, several Cat-K inhibitors are currently being studied in clinical trials for the treatment of osteomalacia, osteoporosis, and MBDs ( Lu et al , 2018 ). Odanacatib, an extremely selective and recoverable Cat-K inhibitor, is currently in phase 3 trials ( Xue et al , 2019 ). In phase II clinical trials, it reduced bone resorption, while only temporarily inhibiting bone formation, and its use for five years resulted in significant sequential increases in bone density at the hip and spine ( Lu et al , 2018 ).…”

Section: Problems and Significant Improvements In Drug Therapymentioning

confidence: 99%

Metabolic Bone Diseases and New Drug Developments

Vijayakumar

Kim

2022

Biomol Ther (Seoul)

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Metabolic bone diseases are serious health issues worldwide, since several million individuals over the age of 50 are at risk of bone damage and should be worried about their bone health. One in every two women and one in every four men will break a bone during their lifetime due to a metabolic bone disease. Early detection, raising bone health awareness, and maintaining a balanced healthy diet may reduce the risk of skeletal fractures caused by metabolic bone diseases. This review compiles information on the most common metabolic bone diseases (osteoporosis, primary hyperparathyroidism, osteomalacia, and fluorosis disease) seen in the global population, including their symptoms, mechanisms, and causes, as well as discussing their prevention and the development of new drugs for treatment. A large amount of research literature suggests that balanced nutrition and balanced periodic supplementation of calcium, phosphate, and vitamin D can improve re-absorption and the regrowth of bones, and inhibit the formation of skeletal fractures, except in the case of hereditary bone diseases. Meanwhile, new and improved drug formulations, such as raloxifene, teriparatide, sclerostin, denosumab, and abaloparatide, have been successfully developed and administered as treatments for metabolic bone diseases, while others (romososumab and odanacatib) are in various stages of clinical trials.

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Novel cathepsin K inhibitors block osteoclasts in vitro and increase spinal bone density in zebrafish

Abstract: Cathepsin K (Cat K) is a predominant cysteine protease and highly potent collagenase expressed in osteoclasts.

Cited by 6 publications

References 40 publications

10-Gingerol Suppresses Osteoclastogenesis in RAW264.7 Cells and Zebrafish Osteoporotic Scales

10-Gingerol Suppresses Osteoclastogenesis in RAW264.7 Cells and Zebrafish Osteoporotic Scales

A Review of Signaling Transduction Mechanisms in Osteoclastogenesis Regulation by Autophagy, Inflammation, and Immunity

Metabolic Bone Diseases and New Drug Developments

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