Cathepsin K: The Action in and Beyond Bone

Dai, Rongchen; Wu, Zeting; Chu, Hang Yin; Lü, Jun; Lyu, Aiping; Liu, Jin; Zhang, Ge

doi:10.3389/fcell.2020.00433

Cited by 135 publications

(107 citation statements)

References 142 publications

(207 reference statements)

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“…Cathepsin K is primarily responsible for bone matrix degradation by osteoclasts and is currently the most attractive target for treating osteoporosis ( Dai et al, 2020 ). Because 6-shogaol, a major constituent of ginger, also suppresses osteoclastogenesis by inhibiting CTSK activity ( Villalvilla et al, 2014 ), we tested the CTSK inhibition ability of 10-gingerol and GHE under cell-free conditions.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Lysosomal tra cking plays a critical role in osteoclast-mediated osteolysis [41]. We found that although ATG7, CTSK, and LC3 protein levels were gradually increased during RANKL-induced osteoclastogenesis, CTSK is considered one of the most effective protease, of which main function is to regulate lysosome secretion, thereby promoting bone resorption ability [42]. Alpinetin (20 µM) signi cantly decreased the levels of all these proteins (Fig.…”

Section: Alpinetin Inhibits Lysosomal Biogenesis and Tra Cking By Modmentioning

confidence: 87%

Alpinetin Inhibits RANKL-Induced Osteoclastogenesis and Ovariectomy-Induced Bone Loss by Modulating NFATc1 Transcription and Lysosomal Function

Chen

et al. 2020

Preprint

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BackgroundPostmenopausal osteoporosis is a chronic metabolic bone disease caused by excessive osteoclast activation, and osteoclasts are considered to be the sole participants in the degeneration and resorption of bone matrix for controlling bone integrity and continuity. The biological functions of osteoclasts depend critically on the number and activity of fused polykaryon. Hence, targeting osteoclast differentiation and activity can modulate bone resorption and alleviate osteoporosis. Alpinetin is widely used for excellent anti-inflammatory activities and little side-effect, but its role in osteoporosis remains unknown.ResultsIn this study, we investigated for the first time the ability of alpinetin to inhibit estrogen deficiency-induced bone loss. Alpinetin significantly reduced the expression levels of NFATc1 and its downstream genes, thereby inhibiting osteoclast differentiation in a concentration- and time-dependent manner. Additionally, alpinetin inhibited F-actin ring formation and bone resorption, as well as reduced the activation levels of NF-κB, ERK, and AKT signaling cascades. In mature osteoclasts, alpinetin remarkably inhibited integrin-mediated migration and lysosomal biogenesis and trafficking by modulating the PKCβ/TFEB and ATG5/LC3 axes. Importantly, alpinetin treatment in mice alleviated ovariectomy-induced bone volume loss. ConclusionOur findings strongly suggest that alpinetin plays a significant role in the regulation of NFATc1 production for the differentiation of osteoclasts and inhibits integrin-mediated cell migration and lysosomal function in mature osteoclasts, thus weaken the increased osteolytic ability due to estrogen deficiency. Alpinetin may represent a promising agent for the treatment of osteoporosis and other metabolic bone diseases.

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“…The released protons allow the dissolution of the mineralized components of the bone matrix. The organic matrix made of type I collagen is then broken down by proteases such as Cathepsin K, which can also activate the matrix metalloproteases MMP-9, through cleavage [ 83 , 84 ]. Furthermore, it was recently shown that the deletion of both Mmp9 and Mmp14 genes in bone-marrow-derived myeloid cells altered the bone resorption activity of osteoclasts [ 85 ].…”

Section: Osteoblast/osteoclast Balance In Bone Remodeling and Repamentioning

confidence: 99%

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

Jann

Gascon

Roux

et al. 2020

IJMS

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The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors—in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins—not only regulate the proliferation, differentiation, and functioning of these cells, but also coordinate the communication between them to ensure an appropriate response. Therefore, this review focuses on TGF-β superfamily and its influence on bone formation and repair, through the regulation of osteoclastogenesis, osteogenic differentiation of stem cells, and osteoblasts/osteoclasts balance. After introducing the main types of bone cells, their differentiation and cooperation during bone remodeling and fracture healing processes are discussed. Then, the TGF-β superfamily, its signaling via canonical and non-canonical pathways, as well as its regulation by Wnt/Notch or microRNAs are described and discussed. Its important role in bone homeostasis, repair, or disease is also highlighted. Finally, the clinical therapeutic uses of members of the TGF-β superfamily and their associated complications are debated.

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Cathepsin K: The Action in and Beyond Bone

Cited by 135 publications

References 142 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

Alpinetin Inhibits RANKL-Induced Osteoclastogenesis and Ovariectomy-Induced Bone Loss by Modulating NFATc1 Transcription and Lysosomal Function

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

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