Additionally, direct activation of intracellular signaling can be triggered through several cell-surface receptors, such as integrins, LRP1, LRP6, and Trk A, to which particular ligands other than CCN2 are already specified [7], [10], [23] and [24]. Surprisingly, the direct interaction between the intracellular estrogen receptor and CCN2 and its functional significance have also been recently suggested [22]. As a result of these interactions, CCN2 appears not this website only to participate in the generation of orofacial tissues during development, but also to promote remodeling and regeneration thereafter. The human skull consists of a number of elements of a variety of

sizes and shapes. Upon delivery, the initial skull of a baby is composed of more than 40 elements, which eventually fuse into 22 bones to constitute the adult skull. Among them, the major parts supporting the brain are formed through a developmental pathway entitled endochondral ossification [3] and [25]. Endochondral ossification is a sophisticated biological process established during vertebrate evolution. In this process, bones are primarily formed as cartilage anlagen with comparable shapes. Along the course of development and growth, cartilaginous tissue grows and is gradually replaced with mineralized bone (Fig.

2A). During this process, CCN2 is vigorously produced at the early hypertrophic (prehypertrophic) stage and Epacadostat solubility dmso infiltrates the surrounding extracellular matrix (ECM) toward target cells to accomplish multiple missions [3] and [25]. First, this molecule promotes the proliferation and ECM deposition capability of chondrocytes behind the producers. Second, it accumulates in hypertrophic chondrocytes to accelerate hypertrophy and apoptosis. Third, vascular invasion into the cartilage is promoted by the angiogenic activity of CCN2. Fourth, formation of osteoclasts/chondroclasts can be also promoted by CCN2. Fifth and finally, bone formation by osteoblasts is enhanced by the same factor, as described in the next subsection. These profound roles of CCN2 in

endochondral ossification are represented by the phenotype observed in CCN2-null mice Casein kinase 1 with retarded and abnormal endochondral ossification characterized by impairment of both ECM production and vascular invasion at the growth plate cartilage [26]. Since the cranium is basically a fossil-like structure evolved from an ancient exoskeleton, a significant number of the facial bone components follow a distinct process entitled intramembranous ossification [27]. In this alternative pathway of bone formation, mineralized bone is directly formed by osteoblasts differentiated from mesenchymal stem cells, without forming any intermediate cartilaginous tissue. Recently, CCN2 was shown to be required for this bone-forming process, as well as endochondral ossification in mice.