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.

Early B lymphopoiesis occurs in the bone marrow and is reliant on interactions with numerous cell types in the bone marrow microenvironment, particularly those of the mesenchymal lineage. Each cellular niche that supports the distinct stages of B lymphopoiesis is unique. Different cell types and signaling molecules are important for the progressive stages of B lymphocyte differentiation. Cells expressing CXCL12 and IL-7 have long been recognized as having essential roles in facilitating progression through stages of B lymphopoiesis. Recently, a number of other factors that extrinsically mediate B lymphopoiesis (positively or negatively) have been identified. In addition, the use of transgenic mouse models to delete specific genes in mesenchymal lineage cells has further contributed to our understanding of how B lymphopoiesis is regulated in the bone marrow. This review will cover the current understanding of B lymphocyte niches in the bone marrow and key extrinsic molecules and signaling pathways involved in these niches, with a focus on how mesenchymal lineage cells regulate B lymphopoiesis.