Physiological and Pathophysiological Aspects of Primary Cilia—A Literature Review with View on Functional and Structural Relationships in Cartilage

Barsch, Friedrich; Niedermair, Tanja; Mamilos, Andreas; Schmitt, Volker H.; Grevenstein, David; Babel, Maximilian; Burgoyne, Thomas; Shoemark, Amelia; Brochhausen, Christoph

doi:10.3390/ijms21144959

Cited by 8 publications

(6 citation statements)

References 101 publications

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“…We found no differences in cilium strains between the 0-and 180-degree orientations of cilia in the present study. The orientation of the cilium has been noted to be disrupted in cartilage diseases such as osteoarthritis, osteochondroma, and chondrosarcoma [10,31,32,33]. In the PZ and HZ of growth plate cartilage, primary cilia are present at the top or bottom of the cell and oriented towards the subchondral bone or towards the metaphysis.…”

Section: Discussionmentioning

confidence: 99%

Primary Chondrocyte Cilium Strains Increase with Depth Within the Growth Plate Reserve Zone and Reflect Loading Direction Across the Growth Plate

Carrion¹,

Williams²

2022

Mechanobiol J

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Background. It is known that reserve zone (RZ) chondrocytes regulate the organization of the physis and that chondrocyte primary cilia (PC) act as mechanotransducers. Objective. To explore if physeal loading-induced strains in RZ chondrocyte PC can enable cells to sense whether the physis is subjected to increasing or decreasing levels of compression. Methods. Finite element models of RZ chondrocytes within the physis were created to examine strains developed in the PC when the physis is subjected to either 10% compression or tension. The PC were oriented either toward the epiphysis or metaphysis. Findings. PC basal body axial and transverse strains were negative when the physis was compressed and positive when subjected to tension. Axial strains in the cilium body transition zone also followed the applied loading and were amplified up to 4X, whereas membrane strains transverse to the cilium were tensile under physeal compression, possibly stretching integrin receptors. Tension applied to the physis stretched the cilium membrane in the axial direction. Conclusion. PC perceive strains in ways that may explain the regulatory function of RZ chondrocytes and their role in modulating bone growth.

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Section: Discussionmentioning

confidence: 99%

Primary Chondrocyte Cilium Strains Increase with Depth Within the Growth Plate Reserve Zone and Reflect Loading Direction Across the Growth Plate

Carrion¹,

Williams²

2022

Mechanobiol J

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“…The primary cilium is the center for the Hh signaling transduction; thus, the relationship between cilia and osteochondromas and enchondromas has been investigated. In osteochondroma, the primary cilium incidence was normal, but the cilium orientation was dramatically disrupted compared with control [ 28 ]. Cilium organization is essential for cells' polarity, and the disorganized cilium orientation in most cells of osteochondromas may contribute to the loss of cell polarity and arrangement in the growth plate [ 29 ].…”

Section: Primary Cilia and Ciliary Proteins In Skeletal Diseasesmentioning

confidence: 99%

“…Cilium organization is essential for cells' polarity, and the disorganized cilium orientation in most cells of osteochondromas may contribute to the loss of cell polarity and arrangement in the growth plate [ 29 ]. However, the cilium incidence in enchondroma is reported to vary in different studies [ 28 ]. Ho et al [ 30 ] reported that only 13.4% of cells are ciliated in enchondroma tissues, which significantly decreased compared with control articular cartilage ( Figure 1 ).…”

Section: Primary Cilia and Ciliary Proteins In Skeletal Diseasesmentioning

confidence: 99%

Role of Primary Cilia in Skeletal Disorders

Guo

Shao‐Horn

et al. 2022

Stem Cells International

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Primary cilia are highly conserved microtubule-based organelles that project from the cell surface into the extracellular environment and play important roles in mechanosensation, mechanotransduction, polarity maintenance, and cell behaviors during organ development and pathological changes. Intraflagellar transport (IFT) proteins are essential for cilium formation and function. The skeletal system consists of bones and connective tissue, including cartilage, tendons, and ligaments, providing support, stability, and movement to the body. Great progress has been achieved in primary cilia and skeletal disorders in recent decades. Increasing evidence suggests that cells with cilium defects in the skeletal system can cause numerous human diseases. Moreover, specific deletion of ciliary proteins in skeletal tissues with different Cre mice resulted in diverse malformations, suggesting that primary cilia are involved in the development of skeletal diseases. In addition, the intact of primary cilium is essential to osteogenic/chondrogenic induction of mesenchymal stem cells, regarded as a promising target for clinical intervention for skeletal disorders. In this review, we summarized the role of primary cilia and ciliary proteins in the pathogenesis of skeletal diseases, including osteoporosis, bone/cartilage tumor, osteoarthritis, intervertebral disc degeneration, spine scoliosis, and other cilium-related skeletal diseases, and highlighted their promising treatment methods, including using mesenchymal stem cells. Our review tries to present evidence for primary cilium as a promising target for clinical intervention for skeletal diseases.

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“…Cilia have also been implicated in conditions such as diabetes, cancer, congenital heart disease and osteoarthritis. [3][4][5] As cilia have a near-ubiquitous anatomical distribution, genetic defects affecting the structure or function of cilia cause a range of conditions that can affect multiple organs. Ciliopathies are typically classified into: retinal ciliopathies that exclusively or predominantly affect the eye 6 ; renal ciliopathies, which include autosomal dominant polycystic kidney disease affecting around 1:500 people 7 ; skeletal ciliopathies that cause a diverse range of skeletal dysplasias and cranio-facial dysmorphology 8 ; metabolic or 'obesity' ciliopathies 9 ; neurodevelopmental ciliopathies 10 ; and the respiratory motile ciliopathies.…”

Section: Introductionmentioning

confidence: 99%

“…They encompass a range of severe developmental and degenerative diseases that are individually rare but collectively common, affecting an estimated 15.8 million people worldwide including an estimated 133 000 people in the UK. Cilia have also been implicated in conditions such as diabetes, cancer, congenital heart disease and osteoarthritis 3–5. As cilia have a near-ubiquitous anatomical distribution, genetic defects affecting the structure or function of cilia cause a range of conditions that can affect multiple organs.…”

Section: Introductionmentioning

confidence: 99%

Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project

et al. 2021

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BackgroundPrimary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the ‘cell’s antenna’. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians.MethodsEighty-three prescreened probands were recruited to the 100,000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and ‘Rare Multisystem Ciliopathy Disorders’ (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants.ResultsWe determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL’s automated triaging procedure), which would not be reviewed in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene.ConclusionThese data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data.

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Physiological and Pathophysiological Aspects of Primary Cilia—A Literature Review with View on Functional and Structural Relationships in Cartilage

Cited by 8 publications

References 101 publications

Primary Chondrocyte Cilium Strains Increase with Depth Within the Growth Plate Reserve Zone and Reflect Loading Direction Across the Growth Plate

Primary Chondrocyte Cilium Strains Increase with Depth Within the Growth Plate Reserve Zone and Reflect Loading Direction Across the Growth Plate

Role of Primary Cilia in Skeletal Disorders

Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project

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