Ultrastructural studies have shown that each chondrocyte has such an immotile primary cilium. 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 [37–42]. A physical and chemical deficiency in the chondroblastic and chondrocytic primary cilia results in skeletal and growth plate abnormalities due to improper ECM secretion [43–49]. Integrins, G proteins, and calcium channels on the primary cilium have all been implicated as mechanoreceptors [19, 50–53]. 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 [54–56]. 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 [57] 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 [48].

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) [71–74]. 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. The IFT system is bidirectional and directs movement along the ciliary axoneme. 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.

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. The first hypothesis has been proven to be incorrect by several experiments. For instance, analyses of mutants, such as the Tg737^{orpk Rpw} 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 [79–81].

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 (0.1–1 kPa), MSCs tend to adhere, spread, and exhibit a neurogenic phenotype. MSCs cultured on tenfold stiffer matrices that mimic muscle elasticity (8–17 kPa) become spindle-shaped, similar to myoblasts. When cultured on matrices that mimic the stiffness of bone osteoid (25–40 kPa), the MSC phenotype becomes osteoblast-like with greater expression of osteogenic genes [88]. 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.