the morphological , structural , and material features of the cartilage are genetically programmed but can also be modified by epigenetic factors , such as local tissue stress and strain states [ 1 , 2 ] . mechanical stimulation resulting from weight loading , mobilization , and muscle contraction has an important role in bone formation and normal joint cavitation [ 3 , 4 ] . paralysis of the skeletal musculature is known to inhibit chondrogenesis in developing limbs , which thereby influences the length , mass , and mechanical properties of the forming bone [ 69 ] . the growth plate and articular cartilage are subjected to massive repeated mechanical forces , and they have a limited capacity for repair . thus , understanding how articular cartilage is maintained and how mechanical loads are sensed by the chondrocytes is of primary importance . mechanosensitivity starts with external or internal mechanical responses , and the mechanical stimuli are transduced by the cell into a biochemical outcome . multiple activation mechanisms are simultaneously at play , including the release of autocrine growth factors [ 1017 ] activation of mechanically sensitive kinases , such as src [ 1822 ] focal adhesion kinase ( fak ) [ 2325 ] and extracellular - signal regulated kinase ( erk ) [ 2632 ] and initiation of second messenger signaling [ 33 , 34 ] . mechanical forces drive many cellular events , including proliferation , differentiation , and gene expression in adult differentiated cells and stem cells . when trying to understand how cells can receive a variety of inputs and translate them into a response , we think of a system , or a cell organelle , that can perform these tasks . this organ was shown to have the ability to receive and transduce numerous cell signals . thus , the primary cilium is a good candidate to act as the cell s  control device  for mechanical stimulation because it projects as an  antenna  from the cell into the ecm , and it incorporates integrins , g protein receptors , and calcium channels into the cell membrane . on chondrocytes , the primary cilia are oriented into the pericellular matrix environment of the chondron , and they interact with collagen types ii and iv via receptors [ 3742 ] . a physical and chemical deficiency in the chondroblastic and chondrocytic primary cilia results in skeletal and growth plate abnormalities due to improper ecm secretion [ 4349 ] . integrins , g proteins , and calcium channels on the primary cilium have all been implicated as mechanoreceptors [ 19 , 5053 ] . numerous genes and pathways have been shown to be differentially regulated as a result of mechanical stimuli ; for example , the phosphoinositide 3-kinase / akt , protein kinase a ( pka ) and mitogen - activated protein kinase ( mapk ) pathways [ 5456 ] . it is reasonable to assume that mechanotransduction is a complex multi - component system that allows cells to integrate mechanical stimulations differing in intensity , frequency , duration , and orientation to generate appropriate biological responses , including cartilage formation and regeneration   and , especially , growth - plate formation [ 37 , 58 ] . mice and humans with mutations in ciliary genes often present with defects in skeletal development . two human syndromes that include defects in endochondral bone formation were shown to be associated with mutations in ciliary genes . asphyxiating thoracic dystrophy ( jeune s syndrome ) is associated with a missense mutation in ift80 ( part of ift complex b ) , and it presents with skeletal defects resembling those seen in sonic hedgehog homolog depletion . furthermore , ptc1 ( hh receptor ) expression is downregulated in the ift80 mutant , suggesting that alterations in hh signaling and ellis  van creveld syndrome ( evc ) are characterized by numerous skeletal and craniofacial abnormalities . the mutated protein in evc has been localized to the base of the cilia expressed in chondrocytes and is required for normal hh signaling . the disruption of evc in mice resulted in a variety of skeletal abnormalities associated with diminished ihh signaling . mice mutated in other ciliary genes also demonstrate alterations in endochondral ossification , resulting in a shortening of the long bones . conditional deletion of ift88 or kif3a produces defects in embryonic endochondral bone formation , observed as early as 15.5  days from gestation . when either ift88 or kif3a was deleted at later stages of development using the col2a - cre promoter , the mice demonstrated a progressive loss of the cartilaginous growth plate , resulting in postnatal dwarfism that resembled the phenotype of mice with a conditional deletion of ihh induced in postnatal cartilage . the ihh signaling pathway is one of the major regulatory pathways that lead to chondrocyte division and differentiation in the growth plate . hydrostatic compression of the chondrocytic primary cilium upregulates ihh gene expression [ 49 , 61 , 62 ] . using electron microscopy , it has been shown that the chondrocyte cilium projects into the ecm and is tightly associated with the golgi apparatus [ 39 , 63 ] . integrins have been shown to be present on the chondrocyte cilium , and integrin - dependent signaling cascades have been described in chondrocyte mechanotransduction [ 42 , 64 ] , suggesting a possible role for the chondrocytic cilia in mechanosensing . chondrocytes in articular cartilage differ from those in the growth plate in that they are maintained as mature resting cells . mechanical load is a critical factor in maintaining articular cartilage , but how the load is sensed is not known . recently , the fate of the primary cilia on articular chondrocytes during the progression of bovine oa has been investigated [ 47 , 65 ] . primary cilia were present during all examined stages of oa ; however , the proportion of ciliated cells increased and their orientation towards the surface was altered ; the significance of this orientation remains unclear [ 37 , 63 , 65 ] . recently published cyclic compression experiments proved that mechanical loading modulates chondrocyte primary cilia incidence and length . this observation has been made independent from the well - known reduction of cilia appearance during cell division . axonemal orientation in the cilia of articular chondrocytes is more pronounced in weight - bearing areas compared to of the cartilage tissue [ 66 , 67 ] . chondrocyte proliferation , differentiation , organization , and the major signaling pathways were found to be modified by loading in a chick model . this demonstrated that the mechanical load affected chondrocytes in the growth plate , especially the expression of matrix metalloproteases . primary cilia are non - motile sensory organelles that project from cells in many tissues and types of cells , such as kidney tubules , the bile duct , neurons , the endocrine pancreas , the thyroid , smooth muscle cells , and fibroblasts . the complete list of the cells and tissues containing primary cilia can be found at http://www.bowserlab.org/primarycilia/cilialist.html . in recent years , cilia have emerged as a hot topic in research , resulting in the creation of numerous databases , including those containing genomic and proteomic data on cilium composition ( http://www.ciliaproteome.org , http://www.ciliome.com ) [ 7174 ] . cilia can be seen as specialized cellular compartments or organelles [ 36 , 75 ] . they are microtubule - based structures that originate at the basal body and extend into the extracellular space . the basal body is a modified form of the centriole , an organelle well known for its role as a microtubule organizing center of mitotic spindles . the basal body / centriole migrates toward the cell membrane and acts as a template for ciliogenesis and an anchor for the primary cilium . the centriole only moves towards the cell membrane when it is not involved in mitosis ; thus , cilium generation occurs during the interphase of the cell . the intraflagellar transport ( ift ) system plays a key role in primary cilium formation and maintenance . because no proteins are synthesized in the primary cilium itself , ciliary proteins are targeted to the basal body and transported to the distal tip through the ift complex . ift complexes are trafficked along the axoneme by molecular motor proteins ; they are transported by kinesin ii in the anterograde direction and by dynein ii in the retrograde direction . motile and non - motile , primary cilia have microtubule axoneme cores made up of nine sets of microtubule doublets that provide structure and rigidity . however , primary cilia lack the central pair of microtubules ( thus are designated 9 + 0 ) , while other motile machinery includes the inner and outer dynein arms , radial spokes , and central pair projections ( designated 9 + 2 ) . unlike the motile cilia , of which there can be many per cell , there is only one primary cilium per cell [ 7678 ] . to date , there are three hypotheses regarding the functional importance of the primary cilium : first , the primary cilium is a vestigial organ on the cell ; second , that it inhibits cell division because it sequesters the centriole ; and third , that it is a cellular sensory structure . for instance , analyses of mutants , such as the tg737 mouse , have indicated that a functioning primary cilium is essential for normal development and function , not only of the kidney , but also of many other tissues and organs . hence , ciliary dysfunction might lead to a series of developmental abnormalities and diseases collectively called ciliopathies , including cystic diseases , obesity , and blindness , as well as behavioral , cognitive , and skeletal defects . the second hypothesis seems reasonable because the majority of cells possess primary cilia when they are not undergoing mitosis . additionally , recent studies have demonstrated the accuracy of the third hypothesis : primary cilia have been shown to be highly involved in cell signaling processes because a number of ion channels , transporter proteins , and downstream effector proteins are associated with the cilium [ 7981 ] . the primary cilium is a few micrometers in length , and it detects and interprets signals from the environment , such as odorants , fluid flow , and protein signaling between cells . signaling , the receptor protein and the protein that transmits the message into the cell are localized in the cilia . protein association or dissociation from the cilia controls the signaling pathways , which ultimately trigger responses such as cell division and differentiation . several independent lines of evidence have demonstrated a role for the primary cilium in hh signaling . hh is the master regulator of endochondral ossification in the growth plate , and it determines chondrocyte activity and subsequent bone length [ 8486 ] . upon hh stimulation , both hh receptors , smo and ptch1 , are recruited to the cilium in vitro and in vivo ; gli2 and gli3 , downstream effectors of hh , also localize to the cilium in the developing limbs [ 45 , 87 ] . other pathways that have been shown to regulate chondrocyte activity but have not yet been linked to the cilium are as follows : bone morphogenic proteins , wingless ( wnts ) , fibroblast growth factors , and insulin - like growth factors , all of which are essential for normal cartilage formation . the effects of mechanical forces on mesenchymal stem cell ( msc ) differentiation were examined in a fundamental study of the concept of environmental cell sensing . the study showed that differentiation of mscs is directed by the stiffness of the culture matrix . on soft collagen gels that mimic the elasticity of brain tissue ( 0.11  kpa ) , mscs cultured on tenfold stiffer matrices that mimic muscle elasticity ( 817  kpa ) become spindle - shaped , similar to myoblasts . when cultured on matrices that mimic the stiffness of bone osteoid ( 2540  kpa ) , the msc phenotype becomes osteoblast - like with greater expression of osteogenic genes . this work , along with similar studies , implies that a cell is able to sense its mechanical environment and that mechanical signaling itself can regulate the differentiation of mscs into different tissues . more recently , padmaja tummala et al . identified the presence of primary cilia on mscs and determined their role in msc differentiation . mscs require primary cilia not only during their differentiation but also to maintain the phenotypes of differentiated cells . in addition , there is evidence that msc differentiation into chondrocytes and osteocytes is regulated by mechanical signals . our research group is working on tissue regeneration to elucidate repair mechanisms , especially in oa ( fig .  1 ) and rheumatoid arthritis . oa is a chronic degenerative disease characterized by articular cartilage degeneration , and it is multifactorial in origin . primary cilia are present on chondrocytes , and the percentage of ciliated cells and the lengths of the cilia within oa tissue are higher compared to the normal tissue , although the implications of these facts have yet to be elucidated.fig . 1a electron micrograph of the primary cilium ( ax ) , the distal ( dc ) , and proximal ( pc ) centriole . c schematic presentation of the primary cilium with membrane signaling molecules that were described in it . d human articular chondrocytes and f cpcs stained with acetylated -tubulin ( tb , green ) abs to detect primary cilia ( arrows ) , phalloidin ( ph , red ) and dapi ( dapi , blue ) . e tissue from the late stage of human oa exhibits surface fissures and cell clusters ( the arrow indicates the tidemark ) . breaks in the tidemark are filled with blood vessels , and the bone marrow is visible underneath the oa tissue . reprinted from koelling et al .   with permission from the publisher a electron micrograph of the primary cilium ( ax ) , the distal ( dc ) , and proximal ( pc ) centriole . c schematic presentation of the primary cilium with membrane signaling molecules that were described in it . d human articular chondrocytes and f cpcs stained with acetylated -tubulin ( tb , green ) abs to detect primary cilia ( arrows ) , phalloidin ( ph , red ) and dapi ( dapi , blue ) . e tissue from the late stage of human oa exhibits surface fissures and cell clusters ( the arrow indicates the tidemark ) . breaks in the tidemark are filled with blood vessels , and the bone marrow is visible underneath the oa tissue . reprinted from koelling et al .   with permission from the publisher we have isolated cpcs from subjects in late - stage oa and characterized their role in the repair of diseased articular cartilage . these cells are positive for stem cell markers and exhibit stem cell properties such as clonogenicity , multipotency , and migratory activity . recently , we identified primary cilia projecting from the surfaces of cpcs using antibodies against acetylated alpha tubulin . our laboratory is focused on using mechanobiological approaches to investigate the role of primary cilia in differentiation of cpcs into chondrocytes [ 91 , 92 ] . owing to the involvement of primary cilia in fundamental cellular processes , mutations in primary ciliary proteins result in diverse diseases such as cystic kidney diseases , obesity , and retinal degeneration . recent studies have presented a comprehensive concept that primary cilia are acting as dual sensors for physical and chemical cues . therefore , over the past few years , many researchers have been paying attention to primary cilia to understand their role in development and diseases . here , we have reviewed the basic role of primary cilia in mechanotransduction and their possible impact on cartilaginous tissues . additionally , our results show that primary cilia project not only from the surface of human osteoarthritic chondrocytes but also from the surface of chondrogenic progenitor cells . one future line of research should be to elucidate the role of the primary cilia in chondrogenic differentiation to enhance the potential of cartilage repair .
the primary cilium is an immotile , solitary , and microtubule - based structure that projects from cell surfaces into the extracellular environment . 
 the primary cilium functions as a dual sensor , as mechanosensors and chemosensors . 
 the primary cilia coordinate several essential cell signaling pathways that are mainly involved in cell division and differentiation . 
 a primary cilium malfunction can result in several human diseases . 
 mechanical loading is sense by mechanosensitive cells in nearly all tissues and organs . with this sensation 
 , the mechanical signal is further transduced into biochemical signals involving pathways such as akt , pka , fak , erk , and mapk . in this review , 
 we focus on the fundamental functional and structural features of primary cilia in chondrocytes and chondrogenic cells .