The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated

The one or more molecular mechanisms that determine the obligatory sequence of resorption followed by formation during bone remodeling is unclear. RAN K ligand (RANK-L) is an essential requirement for osteoclastogenesis, and i ts activity is neutralized by binding to the soluble decoy receptor, osteop rotegerin (OPG). Because both molecules are produced by osteoblast lineage cells, we studied their developmental regulation in a conditionally immorta lized human marrow stromal (hMS[2-15]) cell line. These cells can simulate the complete developmental sequence from undifferentiated precursor(s) to c ells with the complete osteoblast phenotype that are capable of forming min eralized nodules. During osteoblast differentiation, RANK-L messenger RNA l evels decreased by 5-fold, whereas OPG messenger RNA levels increased by 7- fold, resulting in a 35-fold change in the RANK-L/OPG ratio. OPG protein al so increased by 6-fold. Mouse hone marrow cells generated osteoclast-like c ells in coculture with undifferentiated hMS(2-15) cells, but did not when c ocultured with hMS(2-15) cells in varying stages of differentiation, unless an excess of RANK-L was added. Thus, undifferentiated marrow stromal cells with a high RANK-L/OPG ratio can initiate and support osteoclastogenesis, but after differentiation to the mature osteoblast phenotype, they cannot. We speculate that the develop mental regulation of OPG and RANK-L productio n by stromal/osteoblast cells contributes to the coordinated sequence of os teoclast and osteoblast differentiation during the hone remodeling cycle.