Retinoic acid stimulates expression of the functional osteoclast integrin αvβ3: Transcriptional activation of the β3 but not the αv gene

Abstract

The capacity of osteoclasts to resorb bone depends, in part, on the surface expression of the integrin alpha v beta 3. We have investigated whether the steroid hormone retinoic acid, known to stimulate bone resorption, regulates the appearance of the alpha v beta 3 complex in avian osteoclast presursors. Using surface labeling, followed by immunoprecipitation with a alpha v beta 3-specific antibody, we show that retinoic acid increases surface expression of the heterodimer in a dose- and time-dependent manner. Northern analysis reveals that the high basal steady-state levels of alpha v mRNA do not change, while those for beta 3 rise significantly from their initially low levels. Nuclear run-on studies confirm that steroid treatment stimulates transcription of the beta 3, but not the alpha v gene. Osteoclast precursors treated with retinoic acid exhibit increased multinucleation and expression of the osteoclast marker enzyme tartrate-resistant acid phosphatase. However, the fused cells do not have an increased capacity to resorb bone. In summary, multinucleated cells generated in this study do not represent fully differentiated bone-resorbing polykaryons. These results suggest that treatment of osteoclast precursors with retinoic acid is necessary, but insufficient, for expression of the mature osteoclast phenotype.

Retinoic acid upregulates β1-integrin in vascular smooth muscle cells and alters adhesion to fibronectin

“…all-trans retinoic acid; cell-adhesion molecules; rat blood vessels RETINOIC ACID (RA) exerts profound effects on embryonic development (8, 17), cellular growth (6, 20, 21, 29), and differentiation (6, 8). Extracellular matrix (ECM) proteins and their receptors, which often control tissue remodeling (11,12,14,15,19,31), are an emerging class of products that are modified by RA treatment (2,5,7,23,25,30). By regulating these molecules, the retinoids control both cell differentiation and growth.…”

“…One mechanism for this inhibition could be the triggering of intracellular signals initiated by specific environmental stimuli that are transduced by cell-matrix interactions. Integrins (11,27), a class of ECM receptors that transduce signals for cell growth and migration, are controlled by RA (5,7,25). In addition, their substrates, such as collagen, matrix proteases, adhesion proteins, and other such molecules that control remodeling, have also been reported to be induced by RA (2,23,30).…”

Contemporary Aspects of Endocrinology

“…In human bone marrow cultures, ATRA has been reported to stimulate formation of osteoclast-like multinucleated cells that are incapable of resorbing bone [Thavarajah et al 1991]. Formation of multinucleated osteoclasts unable to resorb bone has also been reported following ATRA treatment of bone marrow cultures from egg laying hens [Chiba et al 1996]. Scheven and Hamilton [1990] found no effect of ATRA on osteoclast formation in rat bone marrow cultures; however, when Hata et al [1992] stimulated osteoclast formation in rat bone marrow cultures with 1,25(OH) 2 -vitamin D 3 , they found inhibition with ATRA.…”