The primary cilium as a dual sensor of mechanochemical signals in chondrocytes

Muhammad, Hayat; Rais, Yoach; Miosge, Nicolai; Monsonego-Ornan, Efrat

doi:10.1007/s00018-011-0911-3

Cited by 71 publications

(64 citation statements)

References 86 publications

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“…Ultrastructural studies have confirmed that mature chondrocytes possess an immotile primary cilium that has a microtubule axoneme core made up of a ring of nine microtubule doublets, but devoid of the central pair of microtubules (thus designated as 9+0) that motile cilia always have (called a 9+2 axoneme) [26]. Primary cilia have been well documented to serve as a nexus that integrates chemical and mechanical signals; in particular, they are considered as mechanosensors of fluid flow in many cell types including kidney epithelial cells, cholangioctyes or endothelial cells [54].…”

Section: Discussionmentioning

confidence: 98%

“…Primary cilia have been well documented to serve as a nexus that integrates chemical and mechanical signals; in particular, they are considered as mechanosensors of fluid flow in many cell types including kidney epithelial cells, cholangioctyes or endothelial cells [54]. Primary cilia are also present on human mesenchymal stem cells, on arthritic chondroprogenitor cells (CPCs) [26] and on chondrocytes where they are unique sensory organelles that project into the pericellular matrix and interact with their close environment (i.e. collagen types II and IV) via integrins, G proteins, and various Ca 2+ channels; many of which have been implicated as mechanoreceptors [55].…”

Section: Discussionmentioning

confidence: 99%

“…receptors and ion channels that are primarily exposed to mechanical stimuli), including purinergic P2 receptors [21], α5β1 integrins [22], transient receptor potential channel vanilloid-4 [23], N-methyl-D-aspartate type glutamate receptors (NMDAR) [24] and stretch-activated Ca 2+ channels [25]. As far as signalling events downstream of plasma membrane receptors are concerned, the involvement of the Src and focal adhesion kinases (FAK), the extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase/Akt pathways have been reported in various models [26]. Of note, the majority of the above studies were performed on mature articular chondrocytes, rather than differentiating chondrocytes; research aimed at identifying downstream mechanotransduction signalling pathways during chondrogenesis was largely lacking.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Juhász

Matta

Somogyi

et al. 2014

Cellular Signalling

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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.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

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“…Primary cilia in chondrocytes acts as a mechanosensor, (17) and the polycystic kidney disease 2 (Pkd2) gene encodes a mechanoreceptor localized on cilia. Conditional loss of Pkd2 leads to multiple postnatal craniofacial anomalies, including the compression of temporomandibular joints when heads receive a mechanical stress.…”

Section: Discussionmentioning

confidence: 99%

SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice

Kamiya

Shen

Noda³

et al. 2015

Journal of Bone and Mineral Research

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Congenital orofacial abnormalities are clinically seen in human syndromes with SHP2 germline mutations such as LEOPARD and Noonan syndrome. Recent studies demonstrate that SHP2-deficiency leads to skeletal abnormalities including scoliosis and cartilaginous benign tumor metachondromatosis, suggesting that growth plate cartilage is a key tissue regulated by SHP2. The role and cellular mechanism of SHP2 in the orofacial cartilage, however, remains unknown. Here, we investigated the postnatal craniofacial development by inducible disruption of Shp2 in chondrocytes. Shp2 conditional knockout (cKO) mice displayed severe deformity of the mandibular condyle accompanied by disorganized, expanded cartilage in the trabecular bone region, enhanced type X collagen, and reduced Erk production. Interestingly, the length of primary cilia, an antenna like organelle sensing environmental signaling, was significantly shortened, and the number of primary cilia was reduced in the cKO mice. The expression levels of intraflagellar transports (IFTs), essential molecules in the assembly and function of primary cilia, were significantly decreased. Taken together, lack of Shp2 in orofacial cartilage led to severe defects of ciliogenesis through IFT reduction, resulting in mandibular condyle malformation and cartilaginous expansion. Our study provides new insights into the molecular pathogenesis of SHP2-deficiency in cartilage and helps to understand orofacial and skeletal manifestations seen in patients with SHP2 mutations.

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“…Ion channels, integrin signaling, and the primary cilia have all been implicated in transducing the external biophysical environment of chondrocytes into electrical and/or chemical intracellular signaling (7)(8)(9). Specifically, intracellular Ca 2+ signaling has emerged as a common regulatory mechanism for controlling gene and protein expression (10)(11)(12).…”

mentioning

confidence: 99%

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading

O’Conor

Leddy

Benefield

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

363

448

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Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharmacologic therapies for joint diseases. Transient receptor potential vanilloid 4 (TRPV4), a Ca 2+ -permeable osmomechano-TRP channel, is highly expressed in articular chondrocytes, and loss of TRPV4 function is associated with joint arthropathy and osteoarthritis. The goal of this study was to examine the hypothesis that TRPV4 transduces dynamic compressive loading in articular chondrocytes. We first confirmed the presence of physically induced, TRPV4-dependent intracellular Ca 2+ signaling in agarose-embedded chondrocytes, and then used this model system to study the role of TRPV4 in regulating the response of chondrocytes to dynamic compression. Inhibition of TRPV4 during dynamic loading prevented acute, mechanically mediated regulation of proanabolic and anticatabolic genes, and furthermore, blocked the loadinginduced enhancement of matrix accumulation and mechanical properties. Furthermore, chemical activation of TRPV4 by the agonist GSK1016790A in the absence of mechanical loading similarly enhanced anabolic and suppressed catabolic gene expression, and potently increased matrix biosynthesis and construct mechanical properties. These findings support the hypothesis that TRPV4-mediated Ca 2+ signaling plays a central role in the transduction of mechanical signals to support cartilage extracellular matrix maintenance and joint health. Moreover, these insights raise the possibility of therapeutically targeting TRPV4-mediated mechanotransduction for the treatment of diseases such as osteoarthritis, as well as to enhance matrix formation and functional properties of tissue-engineered cartilage as an alternative to bioreactor-based mechanical stimulation. mechanobiology | ion channel | calcium signaling | TGF-beta | tissue engineering

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The primary cilium as a dual sensor of mechanochemical signals in chondrocytes

Cited by 71 publications

References 86 publications

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

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

SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading

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