The best known pair of coupling factors is the receptor activator of NF-κB (RANK) on osteoclast progenitors and the RANK ligand (RANKL) on osteoblasts [40]. Additionally, another pair of cell-surface molecules was more recently nominated as novel coupling factors of bone remodeling, i.e., the ephrin B2 ligand on osteoclasts and the EphB4 receptor tyrosine kinase on osteoblasts [41]. Of interest, ephrin

B2 has also been shown to be produced by periodontal ligament cells Tofacitinib research buy in a strain-dependent manner, indicating its involvement in bone remodeling upon orthodontic tooth movement [42]. Here, another mode of coupling between these cells is proposed (Fig. 4). As described in a previous section, CCN2 is produced by osteoblasts at early stages Linsitinib mw of differentiation and promotes their proliferation and osteoblastic differentiation [28]. Moreover, our recent study revealed that the same CCN2 molecule enhances osteoclastogenesis via interaction with dendritic cell-specific transmembrane protein (DC-STAMP), which is a cell-surface molecule playing a role in the cell fusion events that occur upon the maturation of osteoclasts [43]. In that report, the production of CCN2 by osteoclast progenitors was

confirmed as well. As such, this single molecule, CCN2, is indeed coupling osteoblasts and osteoclasts and modulating the action of both cells; and thus it deserves the title of single DNA ligase coupling factor of bone remodeling. Since CCN2 acts on both types of the cells positively, this factor may be coordinating efficient and balanced bone remodeling. This functional property of CCN2 is well demonstrated by the regenerative effect of CCN2 on bone defects [13]. The fact that mechanical stimuli induce CCN2 production by osteocytes also indicates the property of CCN2 as a coordinator of bone remodeling [44]. Despite that cartilage evolved from a prototypic endoskeleton that supported the body, biological missions assigned to the present permanent cartilage in the human body are quite different from those of bone. Since uncalcified cartilage does not serve as a storage depot for

calcium and phosphate, it is not necessary for cartilage to be continuously remodeled to support calcium homeostasis. Nevertheless, instead of being major skeletal components of the face, our cartilage plays a critical role by enabling flexible movement of our jaws, taking advantage of its elasticity and stiffness. The major role of articular cartilage is to soften the friction and absorb the pressure between the bones upon movement; hence, it is constantly subject to mechanical stress load and minor injury. Therefore, another mode of tissue remodeling does occur in response to these stimuli, in order to maintain the physical properties of articular cartilage. In this context, it is important to mention that CCN2 protein is induced in chondrocytes upon mechanical stress load [45].