Retinoic Acid Receptor γ Activity in Mesenchymal Stem Cells Regulates Endochondral Bone, Angiogenesis, and B Lymphopoiesis

Abstract

Retinoic acid receptor (RAR) signaling regulates bone structure and hematopoiesis through intrinsic and extrinsic mechanisms. This study aimed to establish how early in the osteoblast lineage loss of RARγ (Rarg) disrupts the bone marrow microenvironment. Bone structure was analyzed by micro-computed tomography (μCT) in Rarg mice and mice with Rarg conditional deletion in Osterix-Cre-targeted osteoblast progenitors or Prrx1-Cre-targeted mesenchymal stem cells. Rarg tibias exhibited less trabecular and cortical bone and impaired longitudinal and radial growth. The trabecular bone and longitudinal, but not radial, growth defects were recapitulated in Prrx1:Rarg mice but not Osx1:Rarg mice. Although both male and female Prrx1:Rarg mice had low trabecular bone mass, males exhibited increased numbers of trabecular osteoclasts and Prrx1:Rarg females had impaired mineral deposition. Both male and female Prrx1:Rarg growth plates were narrower than controls and their epiphyses contained hypertrophic chondrocyte islands. Flow cytometry revealed that male Prrx1:Rarg bone marrow exhibited elevated pro-B and pre-B lymphocyte numbers, accompanied by increased Cxcl12 expression in bone marrow cells. Prrx1:Rarg bone marrow also had elevated megakaryocyte-derived Vegfa expression accompanied by smaller sinusoidal vessels. Thus, RARγ expression by Prrx1-Cre-targeted cells directly regulates endochondral bone formation and indirectly regulates tibial vascularization. Furthermore, RARγ expression by Prrx1-Cre-targeted cells extrinsically regulates osteoclastogenesis and B lymphopoiesis in male mice. © 2018 American Society for Bone and Mineral Research.

The Pleiotropic Role of Retinoic Acid/Retinoic Acid Receptors Signaling: From Vitamin A Metabolism to Gene Rearrangements in Acute Promyelocytic Leukemia

“…It has long been known that RARs are nuclear receptors that play an important role in the proliferation and differentiation of numerous cell lines. Several studies have shown that RARs have a direct role both in hematopoiesis and in non-hematopoietic cells present in the bone marrow (BM) microenvironment and which also influence the correct process of hematopoiesis [127] (Figure 2). The utilization of ATRA to differentiate leukemic cells block at the promyelocytic stage in patients with APL is a first example of the importance of retinoids signaling in the process of differentiation of hematopoietic cells [128].…”

<p>The Antagonist of Retinoic Acid Receptor α, ER-50891 Antagonizes the Inhibitive Effect of All-Trans Retinoic Acid and Rescues Bone Morphogenetic Protein 2-Induced Osteoblastogenic Differentiation</p>

“…49,50 RARγ activity in mesenchymal stem cells plays a role in regulating endochondral bone. 51 Green et al report that RARγ is a negative regulator of osteoclastogenesis in vivo and in vitro. 49 However, hitherto, there are few publications reporting the involvement of different receptors in the ATRA's inhibitive effects of BMPinduced osteoblastogenesis.…”

Vitamin A decreases the anabolic bone response to mechanical loading by suppressing bone formation

“…On the endocortical surface, these receptors appear to be expressed in both proliferating preosteoblasts and terminally differentiated osteoblasts. We cannot exclude, however, that the effects on osteoblasts may be due to extrinsic effects mediated by other cell types in the bone microenvironment expressing RARs, because it has recently been shown that deletion in mice of Rarg in Prxx1 -expressing limb bud–derived mesenchymal stem cells results in not only decreased trabecular bone mass but also in effects on angiogenesis and B-lymphopoiesis ( 51 ). It seems that the decrease in cortical thickness observed in mice with global deletion of Rarg may also be caused by extrinsic effects, because this effect was not observed in mice with deletion of Rarg in Prxx1 - or Sp7 -expressing cells.…”