Inhibition of osteoclastogenesis by sex steroids and other nuclear receptor ligands.

摘要

The osteoclast is the primary cell type within the bone marrow that is responsible for the resorption of bone. In a variety of osteopathic bone disorders, bone resorption by osteoclasts outpaces bone formation by osteoblasts leading to local or systemic bone loss. Factors identified as negative regulators of the process of osteoclastogenesis are, therefore, of particular interest due to their potential therapeutic application in the prevention of excessive bone resorption. The present studies investigate the target cells and molecular mechanisms utilized by two factors previously characterized as bone-protective and anti-osteoclastogenic, namely 17β-estradiol (E2) and interleukin-4 (IL-4). Evidence is presented here that both E2 and IL-4 act directly on osteoclast progenitor and precursor cells to inhibit the lineage progression of early hematopoietic cells into mature, differentiated osteoclasts. Further, these studies reveal that the mechanisms used by E2 and IL-4 include nuclear receptor activation and the inhibition of pro-osteoclastogenic signals induced by key regulatory factors such as receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). To assess the biological implications of E2 and IL-4 with respect to regulation of osteoclast formation we used primary murine bone marrow monocytes and the murine monocytic/macrophagic cell line RAW264.7 in a series of osteoclast differentiation assays. The results of these experiments demonstrate that both E2 and IL-4 effectively suppress RANKL/M-CSF induced differentiation of myelomonocytic precursors into osteoclasts via a mechanism that does not require mediation by bone-marrow stromal cells. E2 also suppressed the proliferation of early lymphoid cells, recently identified as potentially important mediators of osteoclast formation. Multiple molecular analyses of the anti-osteoclastogenic action of E2 revealed that E2, via activation of estrogen receptor (ER), blocks RANKL/M-CSF induced transcriptional activation of activator protein-1 (AP-1) through a direct regulation of c-Jun activity. As described here, the action of EL-4 to inhibit osteoclast formation is also mediated via activation of a specific nuclear receptor, peroxisome proliferator activated receptor-gamma (PPARγ), an action that is suggestive of the IL-4 induced synthesis of novel PPARγ ligand(s). E2 and IL-4, therefore, each negatively impact osteoclastogenesis directly via unique cellular mechanisms that include activation of either ER or PPARγ.