Bmp2 gene in osteoblasts of periosteum and trabecular bone links bone formation to vascularization and mesenchymal stem cells

Abstract

SummaryWe generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKO ob ) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO ob mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in a reduced bone formation rate and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKO ob osteoblasts. Deletion of Bmp2 in osteoblasts also leads to defective mesenchymal stem cells (MSCs), which correlates with the reduced microvascular bed in the periosteum and trabecular bones. Expression of several MSC marker genes (a-SMA, CD146 and Angiopoietin-1) in vivo, in vitro CFU assays and deletion of Bmp2 in vitro in a-SMA + MSCs support our conclusions. Critical roles of Bmp2 in osteoblasts and MSCs are a vital link between bone formation, vascularization and mesenchymal stem cells.

Specification of osteoblast cell fate by canonical Wnt signaling requires Bmp2

“…Skeletal stem cells (SSCs) first appear in the limb bud mesenchyme, where Prx1 is broadly expressed, and upon residency in adult bone, produce a variety of secreted niche factors including Bmp2, Wnt3a, TGFβ3 and Grem1 (Chan et al, 2015;Worthley et al, 2015;Yang et al, 2013). Accumulating data suggest that specific skeletal tissue types, such as bone or cartilage, can be induced from SSCs as well as ESCs (Craft et al, 2013) by controlling the timing and combination of growth factors presented to the cell.…”

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

“…[21][22][23] Furthermore, the upregulation of TGF-b and BMP2, which follows the expression of RUNX2, likely further contributes to the amplification of the numbers of osteoblasts. 26,27 In addition, the expression of BMP2 and VEGF may play a role in the development of increased marrow microvessel density. 23,27 The coupling of osteoblast precursors with vascular repair has been previously reported, 52 indicating that osteoblastogenesis and angiogenesis are likely directionally steered by the release of stimulatory signals such as VEGF and BMP2.…”

“…26,27 In addition, the expression of BMP2 and VEGF may play a role in the development of increased marrow microvessel density. 23,27 The coupling of osteoblast precursors with vascular repair has been previously reported, 52 indicating that osteoblastogenesis and angiogenesis are likely directionally steered by the release of stimulatory signals such as VEGF and BMP2. The increased expression of OPG by LCN2-primed MSCs likely contributes to the development of osteosclerosis in MF because OPG promotes additional bone formation by binding to RANKL, thereby preventing osteoclast formation.…”

“…Similarly, the expression of TGF-b and VEGF transcripts (growth factors known to be important in remodeling the MF microenvironment) [24][25][26] was also increased ( Figure 7B), whereas bone morphogenetic protein 2 (BMP2), a member of the TGF-b superfamily involved in osteoblast differentiation, [25][26][27] was increased on day 1 and day 6 of culture. In addition, 2 known products of osteoblasts, osteoprotegerin (OPG) and collagen type 1(COL1A1), 20,21 were also increased after incubation with LCN2 ( Figure 7C).…”

Bone Morphogenetic Protein-2 (BMP-2) Activates NFATc1 Transcription Factor via an Autoregulatory Loop Involving Smad/Akt/Ca2+ Signaling

“…We used the P1 promoter-driven reporter construct for the remainder of our experiments. To determine whether NFATc1 expression is regulated by BMP-2 in vivo, we used tissue sections from a femur of a BMP-2 cKO mouse (38). These mice show reduction in bone mass, radio-opacity, and bone mineral density.…”