Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Wann, A.K.; Knight, Martin M.

doi:10.1007/s00018-012-0980-y

Cited by 116 publications

(168 citation statements)

References 50 publications

Supporting

Mentioning

154

Contrasting

Order By: Relevance

“…Here, we report for the first time to our knowledge a clear PC-1 dosage-dependent increase in cilia length in normal and cystic CDs. Increased cilia length has been associated with enhanced cAMP levels and injury/inflammation, the latter of which may be associated with the observed increase in cilia length within the microhamartoma; however, within the kidney, it is of interest that we observed the length increase independent of the cystogenic state of the tubule (80,99,100). This highlights a potential direct role of PC-1 in cilia maintenance.…”

Section: Methodsmentioning

confidence: 67%

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

et al. 2012

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1 +/null mice are normal, Pkd1 RC/null mice have rapidly progressive disease, and Pkd1 RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkd1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/ trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.

show abstract

Section: Methodsmentioning

confidence: 67%

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

et al. 2012

View full text Add to dashboard Cite

show abstract

“…collagen types II and IV) via integrins, G proteins, and various Ca 2+ channels; many of which have been implicated as mechanoreceptors [55]. Furthermore, the PKA pathway has been recently reported to be involved in the regulation of the primary cilium length in chondrocytes [56].…”

Section: Discussionmentioning

confidence: 99%

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Juhász

Matta

Somogyi

et al. 2014

Cellular Signalling

View full text Add to dashboard Cite

Biomechanical stimuli play important roles in the formation of articular cartilage during early foetal life, and optimal mechanical load is a crucial regulatory factor of adult chondrocyte metabolism and function. In this study, we undertook to analyse mechanotransduction pathways during in vitro chondrogenesis. Chondroprogenitor cells isolated from limb buds of 4-day-old chicken embryos were cultivated as high density cell cultures for 6 days. Mechanical stimulation was carried out by a self-designed bioreactor that exerted uniaxial intermittent cyclic load transmitted by the culture medium as hydrostatic pressure and fluid shear to differentiating cells. The loading scheme (0.05 Hz, 600 Pa; for 30 min) was applied on culturing days 2 and 3, when final commitment and differentiation of chondroprogenitor cells occurred in this model. The applied mechanical load significantly augmented cartilage matrix production and elevated mRNA expression of several cartilage matrix constituents, including collagen type II and aggrecan core protein, as well as matrixproducing hyaluronan synthases through enhanced expression, phosphorylation and nuclear signals of the main chondrogenic transcription factor Sox9. Along with increased cAMP levels, a significantly enhanced protein kinase A (PKA) activity was also detected and CREB, the archetypal downstream transcription factor of PKA signalling, exhibited elevated phosphorylation levels and stronger nuclear signals in response to mechanical stimuli. All the above effects were diminished by the PKA-inhibitor H89. Inhibition of the PKA-independent cAMP-mediators Epac1 and Epac2 with HJC0197 resulted in enhanced cartilage formation, which was additive to that of the mechanical stimulation, implying that the chondrogenesispromoting effect of mechanical load was independent of Epac. At the same time, PP2A activity was reduced following mechanical load and treatments with the PP2A-inhibitor okadaic acid were able to mimic the effects of the intervention. Our results indicate that proper mechanical stimuli augment in vitro cartilage formation via promoting both Juhász and Matta et al. 3 differentiation and matrix production of chondrogenic cells, and the opposing regulation of the PKA/CREB-Sox9 and the PP2A signalling pathways is crucial in this phenomenon.

show abstract

“…IL-1, highly expressed in OA, induces the elongation of the cilia via a PKA-dependent mechanism in chondrocytes (Wann and Knight 2012). In addition, IL-1 stimulates the secretion of nitric oxide, PGE 2 , and inflammatory chemokines.…”

Section: Primary Cilia/ift In Osteoarthritismentioning

confidence: 99%

Primary Cilia and Intraflagellar Transport Proteins in Bone and Cartilage

Yuan

Yang

2016

J Dent Res

View full text Add to dashboard Cite

Primary cilia, present on most mammalian cells, function as a sensor to sense the environment change and transduce signaling. Loss of primary cilia causes a group of human pleiotropic syndromes called Ciliopathies. Some of the ciliopathies display skeletal dysplasias, implying the important role of primary cilia in skeletal development and homeostasis. Emerging evidence has shown that loss or malfunction of primary cilia or ciliary proteins in bone and cartilage is associated with developmental and function defects. Intraflagellar transport (IFT) proteins are essential for cilia formation and/or function. In this review, we discuss the role of primary cilia and IFT proteins in the development of bone and cartilage, as well as the differentiation and mechanotransduction of mesenchymal stem cells, osteoblasts, osteocytes, and chondrocytes. We also include the role of primary cilia in tooth development and highlight the current advance of primary cilia and IFT proteins in the pathogenesis of cartilage diseases, including osteoarthritis, osteosarcoma, and chondrosarcoma.

show abstract

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Cited by 116 publications

References 50 publications

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Primary Cilia and Intraflagellar Transport Proteins in Bone and Cartilage

Contact Info

Product

Resources

About