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Retinoids inhibit differentiation of hematopoetic osteoclast progenitors

H. Herschel Conaway^*, Emma Persson, Marie Halén, Susanne Granholm, Olle Svensson, Ulrika Pettersson, Anita Lie and Ulf H. Lerner^,1

^* Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; and

Department of Oral Cell Biology,

Department of Orthopedic Surgery, and

Department of Clinical Pharmacology, Umeå University, Umeå, Sweden

¹ Correspondence: Department of Oral Cell Biology, University of Umeå, SE-901 87 UMEÅ, Sweden. E-mail: ulf.lerner{at}odont.umu.se

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 (IC₅₀ = 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 RAR, with no involvement of PPARβ/. The results suggest that activation of RAR by retinoids in myeloid hematopoietic precursor cells decreases osteoclast formation by altering expression of the transcription factors c-Fos, NFAT2, and MafB.—Conaway, H. H., Persson, E., Halén, M., Granholm, S., Svensson, O., Pettersson, U., Lie, A., Lerner, U. H. Retinoids inhibit differentiation of hematopoetic osteoclast progenitors.

Key Words: osteoporosis • c-Fos • NFAT2 • ATRA