Abstract
Bone morphogenetic protein (Bmp) signaling is critical for organismal development and homeostasis. To elucidate Bmp2 function in the vascular/hematopoietic lineages we generated a new transgenic mouse line in which ectopic Bmp2 expression is controlled by the Tie2 promoter. Tie2CRE/+;Bmp2tg/tg mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably, Tie2CRE/+;Bmp2tg/tg mice develop extensive soft tissue bone formation typical of acquired forms of heterotopic ossification (HO) and genetic bone disorders, such as Fibrodysplasia Ossificans Progressiva (FOP). Ectopic ossification in Tie2CRE/+;Bmp2tg/tg transgenic animals is accompanied by increased bone marrow hematopoietic, fibroblast and osteoblast precursors and circulating pro-inflammatory cells. Transplanting wild-type bone marrow hematopoietic stem cells into lethally irradiated Tie2CRE/+;Bmp2tg/tg mice significantly delays HO onset but does not prevent it. Moreover, transplanting Bmp2-transgenic bone marrow into wild-type recipients does not result in HO, but hematopoietic progenitors contribute to inflammation and ectopic bone marrow colonization rather than to endochondral ossification. Conversely, aberrant Bmp2 signaling activity is associated with fibroblast accumulation, skeletal muscle fiber damage, and expansion of a Tie2+ fibro-adipogenic precursor cell population, suggesting that ectopic bone derives from a skeletal muscle resident osteoprogenitor cell origin. Thus, Tie2CRE/+;Bmp2tg/tg mice recapitulate HO pathophysiology, and might represent a useful model to investigate therapies seeking to mitigate disorders associated with aberrant extra-skeletal bone formation.
Highlights
Bone morphogenetic proteins (BMPs) regulate fundamental processes in development and organismal homeostasis [1]
Tie2CRE/+; Bmp2tg/tg mice showed shortened pulmonary acceleration time total bone marrow (BM) cell number was increased in Tie2CRE/+;Bmp2tg/tg mice (Fig. 3A, left panel), there were important variations in the total hematopoietic cell number in ectopic bone (Fig. 3A, right panel) due to uneven Heterotopic ossification (HO) in individual animals
Hematopoietic/endothelial Bmp2 overexpression causes a HO During these studies, we found that Tie2CRE/+;Bmp2tg/tg mice
Summary
Bone morphogenetic proteins (BMPs) regulate fundamental processes in development and organismal homeostasis [1]. During canonical Bmp signaling, BMPs ligands bind to BMP type I receptors (BMPRIs), or activin-like kinase (ALK) 2,3, or 6. This complex binds to BMP type II receptor (BMPRII), which phosphorylates BMPRI, which in turn phosphorylates regulatory-Smads (Smad1/5/8). BMPs were discovered owing to their fundamental role in bone formation and homeostasis [1], and BMP2 is critical for chondrocyte proliferation and endochondral bone maturation, and necessary for bone fracture healing [3, 4]. HO occurs through intramembranous and endochondral bone formation, resembling fracture repair processes. The woven bone gives way to the lamellar bone and marrow stroma, with hematopoietic progenitors, adipocytes, osteoblasts and osteoclasts, while capillary-like vessels give rise to bone marrow (BM) sinusoid-type vessels
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