Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families

T Suda, N Takahashi, N Udagawa, E Jimi… - Endocrine …, 1999 - academic.oup.com
T Suda, N Takahashi, N Udagawa, E Jimi, MT Gillespie, TJ Martin
Endocrine reviews, 1999academic.oup.com
OSTEOCLASTS, which are present only in bone, are multinucleated giant cells with the
capacity to resorb mineralized tissues. During the past decade, several new approaches
have been developed to investigate osteoclast biology. A coculture system of mouse
osteoblasts/stromal cells and hemopoietic cells for osteoclast formation has established the
concept that osteoblasts/stromal cells are crucially involved in osteoclast development. Cell-
to-cell contact between cells of the osteoblast lineage and hemopoietic cells is necessary for …
OSTEOCLASTS, which are present only in bone, are multinucleated giant cells with the capacity to resorb mineralized tissues. During the past decade, several new approaches have been developed to investigate osteoclast biology. A coculture system of mouse osteoblasts/stromal cells and hemopoietic cells for osteoclast formation has established the concept that osteoblasts/stromal cells are crucially involved in osteoclast development. Cell-to-cell contact between cells of the osteoblast lineage and hemopoietic cells is necessary for inducing differentiation of osteoclasts. It has been proposed that osteoblasts/stromal cells express osteoclast differentiation factor (ODF) or stromal osteoclast forming activity (SOFA) as a membrane-associated factor in response to several osteotropic factors such as 1α, 25-dihydroxyvitamin D3 [1α, 25 (OH) 2D3], PTH, and interleukin 11 (IL-11). Osteoclast precursors of the monocyte-macrophage lineage recognize ODF/SOFA through cell-to-cell interaction with osteoblasts/stromal cells, and then differentiate into osteoclasts. Osteoblasts/stromal cells also play an essential role in the activation of osteoclast function. We emphasize that the term “osteoblasts/stromal cells” is an operational one, used for convenience to describe those cells of the osteoblast lineage that have been shown convincingly in vitro to determine osteoclast formation. It is not certain in vivo which members of the lineage cells are responsible. In vitro data suggest that the osteoblast property is progressively lost with maturation of the osteoblast lineage cells, and in vivo, it is not at all likely that mature, synthesizing osteoblasts make any contribution to osteoclast formation. Nor are osteocytes likely to do so, but likely potential contributors are lining cells and early members of the osteoblast lineage that are situated close to the endosteal surface. Ultimately, the process of osteoclast formation is dependent on hemopoietic precursors being presented to the appropriate osteoblasts/stromal cells in an environment that provides appropriate stimulatory factors.
Recently, three laboratories independently cloned cDNAs encoding the identical proteins, giving it the names osteoprotegerin (OPG), osteoclastogenesis inhibitory factor (OCIF), and tumor necrosis factor (TNF) receptor-like molecule 1 (TR1). This protein inhibits osteoclast development in vitro and in vivo. In an attempt to adopt a uniform nomenclature for this important biological activity, we propose that the name of choice be “osteoprotegerin.” OPG is a member of the TNF receptor family, but it does not have a transmembrane domain and possesses a signal sequence, suggesting that OPG functions as a secreted factor. Since OPG has the capacity to limit osteoclast formation, the ligand for this receptor was proposed to be the long-sought-after ODF/SOFA. Indeed, this hypothesis dictated the experiments carried out by the groups who subsequently identified a membrane-bound TNF-like ligand with the capacity to differentiate hematopoietic cells into functional osteoclasts. cDNA libraries from cell lines, which expressed specific binding sites for OPG, were screened by expression cloning approaches. As expected, the binding molecule of OPG was
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