The ciliary protein IFT88 controls post-natal cartilage thickness and influences development of osteoarthritis

Coveney, Clarissa; Zhu, Longji; Miotla‐Zarebska, Jadwiga; Stott, B.; Parisi, Ida; Batchelor, Vicky; Duarte, C.; Chang, Emer; McSorley, E; Vincent, Tonia L.; Wann, A.K.

doi:10.1101/2020.07.29.225599

Cited by 6 publications

(14 citation statements)

References 51 publications

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“…Understanding the complex role of the primary cilium in articular cartilage in vivo is confounded by the effects of cilia loss on skeletal development. Most recently, Coveney et al used the cartilage-specific inducible deletion of IFT88 to remove cilia in mouse joints after skeletal maturity [11]. These studies confirmed a role for the cilium in the mechanosensitive regulation of matrix production, with defects in cartilage formation/maintenance only apparent in regions of the joint subject to higher levels of loading in aged mice [11].…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, Coveney et al used the cartilage-specific inducible deletion of IFT88 to remove cilia in mouse joints after skeletal maturity [11]. These studies confirmed a role for the cilium in the mechanosensitive regulation of matrix production, with defects in cartilage formation/maintenance only apparent in regions of the joint subject to higher levels of loading in aged mice [11]. In the current study, loss of pkd1/pkd2 expression did not result in a change in the regulation of matrix gene expression in the absence of strain, but it rather inhibited mechanosensitive matrix gene expression (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, pkd2 inactivation specifically in mature mouse osteoblasts leads to osteopenia and these mice exhibit reduced expression of several osteoblast-specific genes markers [37]. Therefore, the in vivo ciliary function of PC2 may similarly prove to be more subtle and contribute to the chondroprotective function of this organelle observed in response to joint trauma [11].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Coveney et al reported that tissue-specific deletion of IFT88 in adolescence results in cartilage thinning associated with an increase in spontaneous arthritis later in adulthood [11]. Moreover, these mice exhibit a greater level of joint damage following the surgical induction of OA, which is indicative of a chondroprotective role for the cilium through modulation of mechanotransduction [11].…”

Section: Introductionmentioning

confidence: 99%

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Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation

Thompson

McFie

Chapple

et al. 2021

IJMS

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Primary cilia and associated intraflagellar transport are essential for skeletal development, joint homeostasis, and the response to mechanical stimuli, although the mechanisms remain unclear. Polycystin-2 (PC2) is a member of the transient receptor potential polycystic (TRPP) family of cation channels, and together with Polycystin-1 (PC1), it has been implicated in cilia-mediated mechanotransduction in epithelial cells. The current study investigates the effect of mechanical stimulation on the localization of ciliary polycystins in chondrocytes and tests the hypothesis that they are required in chondrocyte mechanosignaling. Isolated chondrocytes were subjected to mechanical stimulation in the form of uniaxial cyclic tensile strain (CTS) in order to examine the effects on PC2 ciliary localization and matrix gene expression. In the absence of strain, PC2 localizes to the chondrocyte ciliary membrane and neither PC1 nor PC2 are required for ciliogenesis. Cartilage matrix gene expression (Acan, Col2a) is increased in response to 10% CTS. This response is inhibited by siRNA-mediated loss of PC1 or PC2 expression. PC2 ciliary localization requires PC1 and is increased in response to CTS. Increased PC2 cilia trafficking is dependent on the activation of transient receptor potential cation channel subfamily V member 4 (TRPV4) activation. Together, these findings demonstrate for the first time that polycystins are required for chondrocyte mechanotransduction and highlight the mechanosensitive cilia trafficking of PC2 as an important component of cilia-mediated mechanotransduction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation

Thompson

McFie

Chapple

et al. 2021

IJMS

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“…Taken together our data establish the cilium as a cellular location for ENPP-1 EV shedding. Consistent with a role in cilia, mammalian ENPP1 loss-of-function manifests signs of ciliopathies, such as accelerated ossification, hearing impairment, altered insulin metabolism and immune response [43][44][45][46].…”

Section: Cilia Produce Evs That Carry Nucleic Acid-binding Proteins Sid-2 Enpp-1 and Mcm-3mentioning

confidence: 89%

Tracking extracellular vesicle (EV) cargo as a platform for studying EVomics, signaling, and targeting in vivo

Nikonorova

Wang

Cope

et al. 2021

Preprint

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Extracellular vesicle (EV)-based signaling is a challenge to study, due to EV small size, heterogeneity, and limited information on cargo content in vivo. We present Caenorhabditis elegans as a discovery platform that allows single EV tracking from source to target tissue in living animals. We enriched ciliary EVs using GFP-tagged PKD-2 cargo followed by mass spectrometry analysis to identify 2,888 cargo candidates. By integrating our dataset with single-cell transcriptomic data, we identified EV cargo produced by individual neurons and other cell and tissue types. A single cilium produces multiple EVs with distinct protein content. Ciliary EVs carry nucleic acid binding proteins. We observed transfer of EV cargo from the male reproductive tract to the hermaphrodite uterus during mating, a direct demonstration of animal-to-animal EV targeting.

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Ciliary IFT88 Protects Coordinated Adolescent Growth Plate Ossification From Disruptive Physiological Mechanical Forces

Coveney

Samvelyan

Miotla‐Zarebska

et al. 2020

Journal of Bone and Mineral Research

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Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule-based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88 fl/fl ) in the juvenile and adolescent skeleton using a cartilage-specific, inducible Cre (AggrecanCreER T2 Ift88 fl/fl ). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano-dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces.

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The ciliary protein IFT88 controls post-natal cartilage thickness and influences development of osteoarthritis

Cited by 6 publications

References 51 publications

Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation

Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation

Tracking extracellular vesicle (EV) cargo as a platform for studying EVomics, signaling, and targeting in vivo

Ciliary IFT88 Protects Coordinated Adolescent Growth Plate Ossification From Disruptive Physiological Mechanical Forces

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