Age-related marrow adipogenesis is linked to increased expression of RANKL.

With advancing age bone marrow is progressively replaced with adipose tissue, accompanied by a concomitant decline in bone mass and strength. The mechanism underlying the increase in marrow fat and bone destruction remains elusive. We found that on the way of adipogenic differentiation of marrow stromal cells, receptor activator for NF-κB ligand (Rankl) expression was induced, concomitantly with a down-regulation of osteoprotegerin, which prompted us to hypothesize that cells at a preadipocyte stage express RANKL. This concept was supported by the findings that the early adipogenic transcription factors C/EBPβ and C/EBPδ, but not the late factor peroxisome proliferator-activated receptor γ, bind to the Rankl promoter and stimulate Rankl gene transcription. In fact, when cells isolated from the bone marrow of aging mice were analyzed by flow cytometry, we found that cells expressing the pre-adipocyte marker Pref-1 were RANKL-positive, and the number of these cells was increased with aging, with concomitant down-regulation of osteoprotegerin, and most importantly, that these RANKL(+)/Pref-1(+) marrow cells were capable of generating osteoclasts from bone marrow macrophages. Thus, the capacity of cells at a pre-adipocyte stage to express RANKL via C/EBPβ and C/EBPδ and to support osteoclastogenesis may account partly for the co-progression of fatty marrow and bone destruction with aging.