A novel role for cathepsin K in periosteal osteoclast precursors during fracture repair

Walia, Bhavita; Lingenheld, Elizabeth G.; Duong, Le T.; Sanjay, Archana; Drissi, Hicham

doi:10.1111/nyas.13629

Cited by 23 publications

(18 citation statements)

References 30 publications

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“…Osteoblast-secreted RANK-L binds the RANK receptor on osteoclast precursors, inducing osteoclast differentiation. Activated osteoclasts, in turn, secrete cathepsin K and other cysteine proteinases into the bone matrix, which help to degrade type I collagen, and ultimately result in bone matrix breakdown [ 173 , 174 ]. In addition, TGF-beta and IGF-1, released from the bone matrix, stimulate the cancer cells to produce additional PTHrP [ 28 , 175 ].…”

Section: The ‘Vicious Cycle’ Of Cancer Metastasis To Bonementioning

confidence: 99%

Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

Shupp

Kolb

Mukhopadhyay

et al. 2018

Cancers

107

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The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between bone resorption and deposition is upset. Osteoblasts play an important role in bone homeostasis by depositing new bone osteoid into resorption pits. It is becoming increasingly evident that osteoblasts additionally play key roles in cancer cell dissemination to bone and subsequent metastasis. Our laboratory has evidence that when osteoblasts come into contact with disseminated breast cancer cells, the osteoblasts produce factors that initially reduce breast cancer cell proliferation, yet promote cancer cell survival in bone. Other laboratories have demonstrated that osteoblasts both directly and indirectly contribute to dormant cancer cell reactivation in bone. Moreover, we have demonstrated that osteoblasts undergo an inflammatory stress response in late stages of breast cancer, and produce inflammatory cytokines that are maintenance and survival factors for breast cancer cells and osteoclasts. Advances in understanding interactions between osteoblasts, osteoclasts, and bone metastatic cancer cells will aid in controlling and ultimately preventing cancer cell metastasis to bone.

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Section: The ‘Vicious Cycle’ Of Cancer Metastasis To Bonementioning

confidence: 99%

Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

Shupp

Kolb

Mukhopadhyay

et al. 2018

Cancers

107

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“…We also found that the increase of angiogenesis induced by A. muciniphila was mainly attributed to the formation of type H vessels, which highlighted the importance of type H vessels in fracture healing. PDGF-BB, which has been proven to benefit vessel formation and fracture healing ( Walia et al, 2018 ), was also detected in callus of A. muciniphila -treated mice. These data suggest that the increased number of PDGF-BB + preosteoclasts induced by A. muciniphila might stimulate the formation of CD31 hi Emcn hi vessels in callus.…”

Section: Discussionmentioning

confidence: 95%

Akkermansia muciniphila promotes type H vessel formation and bone fracture healing by reducing gut permeability and inflammation

Liu

Tao

Luo

et al. 2020

Disease Models &Amp; Mechanisms

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Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila (A. muc), a gut probiotic, ameliorates systemic inflammation by tightening intestinal barrier. In this study, fractured mice intragastrically administrated with A. muc were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muc at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis and can be stimulated by PDGF-BB. Moreover, A. muc treatment significantly reduced gut permeability and inflammation at early stage. Dextran Sulfate Sodium (DSS) was used to disrupt the gut barrier to determine the role of gut barrier in fracture healing and whether A. muc still can stimulate bone fracture healing. As expected, A. muc evidently improved gut barrier, reduced inflammation, and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muc reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB positive preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidences about the involvement of type H vessels in fracture healing and suggests the potential of A. muc as a promising strategy for bone healing.

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“…A hole was made in the femoral intramedullary canal at the intracondylar notch using a 25-gauge needle, and a 0.015-in.-diameter stainless steel pin was inserted into the intramedullary canal to stabilize the left femur prior to fracture. A closed mid-diaphyseal femoral fracture was produced by a 3-point bending fracture device [ 13 , 14 ]. The limbs were radiographed (Faxitron, Wheeling, IL) immediately after fracture to ensure proper pin placement and subsequently to verify fracture.…”

Section: Methodsmentioning

confidence: 99%

Comparative transcriptomic analysis identifies distinct molecular signatures and regulatory networks of chondroclasts and osteoclasts

et al. 2020

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Background Chondroclasts and osteoclasts have been previously identified as the cells capable of resorbing mineralized cartilage and bone matrices, respectively. While both cell types appear morphologically similar, contain comparable ultrastructural features, and express tartrate-resistant acid phosphatase (TRAP), however, no information is available about the genomic similarities and differences between osteoclasts and chondroclasts. Methods To address this question, we laser captured homogeneous populations of TRAP-positive cells that interact with bone (osteoclasts) and TRAP-positive cells that interact with mineralized cartilage (chondroclasts) on the same plane from murine femoral fracture callus sections. We then performed a global transcriptome profiling of chondroclasts and osteoclasts by utilizing a mouse genome Agilent GE 4X44K V2 microarray platform. Multiple computational approaches and interaction networks were used to analyze the transcriptomic landscape of osteoclasts and chondroclasts. Results Our systematic and comprehensive analyses using hierarchical clustering and principal component analysis (PCA) demonstrate that chondroclasts and osteoclasts are transcriptionally distinct cell populations and exhibit discrete transcriptomic signatures as revealed by multivariate analysis involving scatter plot, volcano plot, and heatmap analysis. TaqMan qPCR was used to validate the microarray results. Intriguingly, the functional enrichment and integrated network analyses revealed distinct Gene Ontology terms and molecular pathways specific to chondroclasts and osteoclasts and further suggest that subsets of metabolic genes were specific to chondroclasts. Protein-protein interaction (PPI) network analysis showed an abundance of structured networks of metabolic pathways, ATP synthesis, and proteasome pathways in chondroclasts. The regulatory network analysis using transcription factor-target gene network predicted a pool of genes including ETV6, SIRT1, and ATF1 as chondroclast-specific gene signature. Conclusions Our study provides an important genetic resource for further exploration of chondroclast function in vivo. To our knowledge, this is the first demonstration of genetic landscape of osteoclasts from chondroclasts identifying unique molecular signatures, functional clustering, and interaction network.

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A novel role for cathepsin K in periosteal osteoclast precursors during fracture repair

Cited by 23 publications

References 30 publications

Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

Akkermansia muciniphila promotes type H vessel formation and bone fracture healing by reducing gut permeability and inflammation

Comparative transcriptomic analysis identifies distinct molecular signatures and regulatory networks of chondroclasts and osteoclasts

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