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Cell Death and Differentiation Nov 2019Metastasis is a complex process that requires the interaction between tumor cells and their microenvironment. As an important regulator of intestinal microenvironment,...
Metastasis is a complex process that requires the interaction between tumor cells and their microenvironment. As an important regulator of intestinal microenvironment, gut microbiota plays a significant role in the initiation and progression of colorectal cancer (CRC), but the underlying mechanisms remain elusive. In this study, a metastasis-related secretory protein cathepsin K (CTSK) was identified as a vital mediator between the imbalance of intestinal microbiota and CRC metastasis. We implanted MC38 cells into the cecal mesentry of antibiotic-treated mice with intragastrically administration of E. coli to mimic gut microbiota imbalance. The bigger primary tumors and more liver metastatic foci were detected in the E. coli group accompanied with high LPS secretion and CTSK overexpression compared with that in the control group. CTSK contributes to the aggressive phenotype of CRC cells both in vitro and in vivo. Silencing CTSK or administration of Odanacatib, a CTSK-specific inhibitor, totally abolished the CTSK-enhanced migration and motility of CRC cells. Interestingly, the tumor-secreted CTSK could bind to toll-like receptor 4 (TLR4) to stimulate the M2 polarization of tumor-associated macrophages (TAMs) via an mTOR-dependent pathway. Recombinant CTSK could neither stimulate CRC growth and metastasis, nor induce M2 macrophage polarization in TRL4 mice. Meanwhile, CTSK could stimulate the secretion of cytokines by M2 TAMs including IL10 and IL17, which, in turn, promote the invasion and metastasis of CRC cells through NFκB pathway. Clinically, overexpression of CTSK in human CRC tissues is always accompanied with high M2 TAMs in the stroma, and correlated with CRC metastasis and poor prognosis. Our current research identified CTSK as a mediator between the imbalance of gut microbiota and CRC metastasis. More importantly, we illustrated a CTSK-mediated-positive feedback loop between CRC cells and TAMs during metastasis, prompting CTSK as a novel predictive biomarker and feasible therapeutic target for CRC.
Topics: Animals; Cathepsin K; Cell Line, Tumor; Colorectal Neoplasms; Escherichia coli; Female; Gastrointestinal Microbiome; HCT116 Cells; HT29 Cells; Heterografts; Humans; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Prognosis; Toll-Like Receptor 4; Tumor Microenvironment
PubMed: 30850734
DOI: 10.1038/s41418-019-0312-y -
The Journal of Clinical Investigation Dec 2020Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin...
Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk+Scx+ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cathepsin K; Gene Expression Regulation, Enzymologic; Hedgehog Proteins; Mice; Mice, Transgenic; Ossification, Heterotopic; Repressor Proteins; Signal Transduction; Stem Cells; Tendons
PubMed: 32853181
DOI: 10.1172/JCI132518 -
Nature Oct 2018Bone consists of separate inner endosteal and outer periosteal compartments, each with distinct contributions to bone physiology and each maintaining separate pools of...
Bone consists of separate inner endosteal and outer periosteal compartments, each with distinct contributions to bone physiology and each maintaining separate pools of cells owing to physical separation by the bone cortex. The skeletal stem cell that gives rise to endosteal osteoblasts has been extensively studied; however, the identity of periosteal stem cells remains unclear. Here we identify a periosteal stem cell (PSC) that is present in the long bones and calvarium of mice, displays clonal multipotency and self-renewal, and sits at the apex of a differentiation hierarchy. Single-cell and bulk transcriptional profiling show that PSCs display transcriptional signatures that are distinct from those of other skeletal stem cells and mature mesenchymal cells. Whereas other skeletal stem cells form bone via an initial cartilage template using the endochondral pathway, PSCs form bone via a direct intramembranous route, providing a cellular basis for the divergence between intramembranous versus endochondral developmental pathways. However, there is plasticity in this division, as PSCs acquire endochondral bone formation capacity in response to injury. Genetic blockade of the ability of PSCs to give rise to bone-forming osteoblasts results in selective impairments in cortical bone architecture and defects in fracture healing. A cell analogous to mouse PSCs is present in the human periosteum, raising the possibility that PSCs are attractive targets for drug and cellular therapy for skeletal disorders. The identification of PSCs provides evidence that bone contains multiple pools of stem cells, each with distinct physiologic functions.
Topics: Animals; Bone Development; Bone and Bones; Cathepsin K; Cell Differentiation; Female; Femur; Fracture Healing; Gene Expression Regulation; Humans; Male; Mesenchymal Stem Cells; Mice; Osteoblasts; Periosteum; Skull; Stem Cells
PubMed: 30250253
DOI: 10.1038/s41586-018-0554-8 -
Nature Medicine Nov 2014Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and...
Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase-positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31(hi)Emcn(hi) vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31(hi)Emcn(hi) vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31(hi)Emcn(hi) vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.
Topics: Acid Phosphatase; Animals; Becaplermin; Cathepsin K; Cell Count; Cell Movement; Culture Media, Conditioned; Endothelial Cells; Female; Femur; Focal Adhesion Protein-Tyrosine Kinases; Isoenzymes; Mesenchymal Stem Cells; Mice, Inbred C57BL; Neovascularization, Physiologic; Osteoclasts; Osteogenesis; Ovariectomy; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Protease Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Tartrate-Resistant Acid Phosphatase; X-Ray Microtomography
PubMed: 25282358
DOI: 10.1038/nm.3668 -
Cell Death & Disease Jun 2023The Raptor signaling pathway is a critical point of intervention in the invasion and progression of cancer. The non-receptor tyrosine kinase Src-mediated phosphorylation...
The Raptor signaling pathway is a critical point of intervention in the invasion and progression of cancer. The non-receptor tyrosine kinase Src-mediated phosphorylation of OTUB1-Y26 plays a critical role in Raptor stabilization, whereas cathepsin K inhibitor (odanacatib; ODN) and knockdown (siRNA) induce Raptor destabilization. However, the mechanisms involved in cathepsin K inhibition-induced OTUB1-Y26 phosphorylation in Raptor stabilization have not been yet elucidated. This study showed that cathepsin K inhibition activates SHP2, a tyrosine phosphatase, that dephosphorylates OTUB1 and destabilizes Raptor, whereas SHP2 deletion and pharmacological inhibition increase OTUB1-Y26 phosphorylation and Raptor expression. SHP2 deletion also led to the inhibition of ODN-induced mitochondrial ROS, fusion, and dysfunction. Furthermore, cathepsin K inhibition phosphorylated spleen tyrosine kinase (Syk) at Y525 and Y526, resulting in the SHP2-mediated dephosphorylation of OTUB1-Y26. Collectively, our findings identified Syk not only as an upstream tyrosine kinase required for SHP2 activation but also showed a critical mechanism that regulates ODN-induced Raptor downregulation and mitochondrial dysfunction. In conclusion, Syk/SHP2/Src/OTUB1 axis-mediated signaling can act as a therapeutic target in cancer management.
Topics: Cathepsin K; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction; Protein-Tyrosine Kinases; Phosphorylation; Mitochondria
PubMed: 37330581
DOI: 10.1038/s41419-023-05884-z -
International Journal of Molecular... Nov 2022Cathepsin K (CatK) is a part of the family of cysteine proteases involved in many important processes, including the degradation activity of collagen 1 and elastin in... (Review)
Review
Cathepsin K (CatK) is a part of the family of cysteine proteases involved in many important processes, including the degradation activity of collagen 1 and elastin in bone resorption. Changes in levels of CatK are associated with various pathological conditions, primarily related to bone and cartilage degradation, such as pycnodysostosis (associated with CatK deficiency), osteoporosis, and osteoarthritis (associated with CatK overexpression). Recently, the increased secretion of CatK is being highly correlated to vascular inflammation, hypersensitivity pneumonitis, Wegener granulomatosis, berylliosis, tuberculosis, as well as with tumor progression. Due to the wide spectrum of diseases in which CatK is involved, the design and validation of active site-specific inhibitors has been a subject of keen interest in pharmaceutical companies in recent decades. In this review, we summarized the molecular background of CatK and its involvement in various diseases, as well as its clinical significance for diagnosis and therapy.
Topics: Cathepsin K; Collagen Type I; Bone and Bones; Cysteine Proteases
PubMed: 36430239
DOI: 10.3390/ijms232213762 -
The Journal of Biological Chemistry Mar 2013Interstitial collagen mechanical and biological properties are altered by proteases that catalyze the hydrolysis of the collagen triple-helical structure. Collagenolysis... (Review)
Review
Interstitial collagen mechanical and biological properties are altered by proteases that catalyze the hydrolysis of the collagen triple-helical structure. Collagenolysis is critical in development and homeostasis but also contributes to numerous pathologies. Mammalian collagenolytic enzymes include matrix metalloproteinases, cathepsin K, and neutrophil elastase, and a variety of invertebrates and pathogens possess collagenolytic enzymes. Components of the mechanism of action for the collagenolytic enzyme MMP-1 have been defined experimentally, and insights into other collagenolytic mechanisms have been provided. Ancillary biomolecules may modulate the action of collagenolytic enzymes.
Topics: Animals; Arthritis; Binding Sites; Catalysis; Cathepsin K; Collagen; Gene Expression Regulation, Enzymologic; Humans; Leukocyte Elastase; Matrix Metalloproteinase 1; Matrix Metalloproteinases; Metabolism; Molecular Conformation; Neoplasms; Protein Binding; Protein Structure, Tertiary; Serine; Substrate Specificity
PubMed: 23430258
DOI: 10.1074/jbc.R113.451211 -
Current Oncology (Toronto, Ont.) Aug 2022Cancer, a common malignant disease, is one of the predominant causes of diseases that lead to death. Additionally, cancer is often detected in advanced stages and cannot... (Review)
Review
Cancer, a common malignant disease, is one of the predominant causes of diseases that lead to death. Additionally, cancer is often detected in advanced stages and cannot be radically cured. Consequently, there is an urgent need for reliable and easily detectable markers to identify and monitor cancer onset and progression as early as possible. Our aim was to systematically review the relevant roles of cathepsin K (CTSK) in various possible cancers in existing studies. CTSK, a well-known key enzyme in the bone resorption process and most studied for its roles in the effective degradation of the bone extracellular matrix, is expressed in various organs. Nowadays, CTSK has been involved in various cancers such as prostate cancer, breast cancer, bone cancer, renal carcinoma, lung cancer and other cancers. In addition, CTSK can promote tumor cells proliferation, invasion and migration, and its mechanism may be related to RANK/RANKL, TGF-β, mTOR and the Wnt/β-catenin signaling pathway. Clinically, some progress has been made with the use of cathepsin K inhibitors in the treatment of certain cancers. This paper reviewed our current understanding of the possible roles of CTSK in various cancers and discussed its potential as a biomarker and/or novel molecular target for various cancers.
Topics: Biomarkers; Cathepsin K; Humans; Male; Neoplasms
PubMed: 36005209
DOI: 10.3390/curroncol29080471 -
Endocrine Reviews Aug 2017Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin... (Review)
Review
Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast-bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacologic cathepsin K inhibition leads to continuous increases in bone mineral density for ≤5 years of treatment and improves bone strength at the spine and hip. Compared with other antiresorptive agents, cathepsin K inhibition is nearly equally efficacious for reducing biochemical markers of bone resorption but comparatively less active for reducing bone formation markers. Despite multiple efforts to develop cathepsin K inhibitors, potential concerns related to off-target effects of the inhibitors against other cathepsins and cathepsin K inhibition at nonbone sites, including skin and perhaps cardiovascular and cerebrovascular sites, prolonged the regulatory approval process. A large multinational randomized, double-blind phase III study of odanacatib in postmenopausal women with osteoporosis was recently completed. Although that study demonstrated clinically relevant reductions in fractures at multiple sites, odanacatib was ultimately withdrawn from the regulatory approval process after it was found to be associated with an increased risk of cerebrovascular accidents. Nonetheless, the underlying biology and clinical effects of cathepsin K inhibition remain of considerable interest and could guide future therapeutic approaches for osteoporosis.
Topics: Cathepsin K; Enzyme Inhibitors; Humans; Osteoporosis
PubMed: 28651365
DOI: 10.1210/er.2015-1114 -
Current Osteoporosis Reports Aug 2019In perilacunar/canalicular remodeling (PLR), osteocytes dynamically resorb, and then replace, the organic and mineral components of the pericellular extracellular... (Review)
Review
PURPOSE OF REVIEW
In perilacunar/canalicular remodeling (PLR), osteocytes dynamically resorb, and then replace, the organic and mineral components of the pericellular extracellular matrix. Given the enormous surface area of the osteocyte lacuna-canalicular network (LCN), PLR is important for maintaining homeostasis of the skeleton. The goal of this review is to examine the motivations and critical considerations for the analysis of PLR, in both in vitro and in vivo systems.
RECENT FINDINGS
Morphological approaches alone are insufficient to elucidate the complex mechanisms regulating PLR in the healthy skeleton and in disease. Understanding the role and regulation of PLR will require the incorporation of standardized PLR outcomes as a routine part of skeletal phenotyping, as well as the development of improved molecular and cellular outcomes. Current PLR outcomes assess PLR enzyme expression, the LCN, and bone matrix composition and organization, among others. Here, we discuss current PLR outcomes and how they have been applied to study PLR induction and suppression in vitro and in vivo. Given the role of PLR in skeletal health and disease, integrated analysis of PLR has potential to elucidate new mechanisms by which osteocytes participate in skeletal health and disease.
Topics: Bone Matrix; Bone Remodeling; Carbonic Anhydrases; Cathepsin K; Cell Line; Homeostasis; Humans; Hydrogen-Ion Concentration; Imaging, Three-Dimensional; Matrix Metalloproteinases; Microscopy, Confocal; Microscopy, Electron, Scanning; Osteocytes; Proton-Translocating ATPases; X-Ray Microtomography
PubMed: 31227998
DOI: 10.1007/s11914-019-00514-0