Retinoids inhibit differentiation of hematopoietic osteoclast progenitors.
Whether vitamin A promotes skeletal fragility, has no effect on fracture rate, or protects against bone loss is unclear. In the present study, effects of retinoids on osteoclast differentiation in cultured mouse bone marrow cells (BMCs), bone marrow macrophages (BMMs), spleen cells, and RAW264.7 cells were evaluated by analyzing osteoclast formation and expression of genes important in signal transduction and osteoclast function. All-trans-retinoic acid (ATRA) did not stimulate osteoclastogenesis in BMCs, but inhibited hormone and RANKL-induced gene expression and formation of osteoclasts. In BMMs, spleen cells, and RAW264.7 cells, osteoclast differentiation and formation stimulated by M-CSF/RANKL were inhibited (IC(50) = 0.3 nM) by ATRA. The effect was exerted at an early step of RANKL-induced differentiation. ATRA also abolished increases of the transcription factors c-Fos and NFAT2 stimulated by RANKL and suppressed down-regulation of the antiosteoclastogenic transcription factor MafB. By comparing effects of several compounds structurally related to ATRA, as well as by using receptor antagonists, evaluation pointed to inhibition being mediated by RARalpha, with no involvement of PPARbeta/delta. The results suggest that activation of RARalpha by retinoids in myeloid hematopoietic precursor cells decreases osteoclast formation by altering expression of the transcription factors c-Fos, NFAT2, and MafB.
Conaway
H Herschel
HH
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Persson
Emma
E
Halén
Marie
M
Granholm
Susanne
S
Svensson
Olle
O
Pettersson
Ulrika
U
Lie
Anita
A
Lerner
Ulf H
UH
D000818:Animals; D002460:Cell Line; D006410:Hematopoiesis / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
D053245:RANK Ligand; D018168:Receptors, Retinoic Acid; D014212:Tretinoin