دانلود رایگان مقاله ضرورت سیگنالینگ BMP برای هموستاز اسکلتی و فعالیت هورمون پاراتیروئید

ABSTRACT

Bmp2 and Bmp4 genes were ablated in adult mice (KO) using a conditional gene knockout technology. Bones were evaluated by microcomputed tomography (μCT), bone strength tester, histomorphometry and serum biochemical markers of bone turnover. Drill-hole was made at femur metaphysis and bone regeneration in the hole site was measured by calcein binding and μCT. Mice were either sham operated (ovary intact) or ovariectomized (OVX), and treated with human parathyroid hormone (PTH), 17β-estradiol (E2) or vehicle. KO mice displayed trabecular bone loss, diminished osteoid formation and reduced biomechanical strength compared with control (expressing Bmp2 and Bmp4). Both osteoblast and osteoclast functions were impaired in KO mice. Bone histomorphomtery and serum parameters established a low turnover bone loss in KO mice. Bone regeneration at the drill-hole site in KO mice was lower than control. However, deletion of Bmp2 gene alone had no effect on skeleton, an outcome similar to that reported previously for deletion of Bmp4 gene. Both PTH and E2 resulted in skeletal preservation in control-OVX, whereas in KO-OVX, E2 but not PTH was effective which suggested that the skeletal action of PTH required Bmp ligands but E2 did not. To determine cellular effects of Bmp2 and Bmp4, we used bone marrow stromal cells in which PTH but not E2 stimulated both Bmp2 and Bmp4 synthesis leading to increased Smad1/5 phosphorylation. Taken together, we conclude that Bmp2 and Bmp4 are essential for maintaining adult skeletal homeostasis and mediating the anabolic action of PTH.

4. Discussion

BMP signaling has critical roles in embryonic development of cartilage [48] and bone [49]. Importance of BMP signaling in bone formation is further supported by the observations that overexpressing BMP antagonists such as noggin [50] or gremlin [51] and deleting gremlin [52] at the embryonic stage in mice resulted in loss and gain of bone formation, respectively. However, what has not been investigated thus far is whether this signaling pathway continues to play an important role in adult skeleton. Mice with limb specific embryonic deletion of Bmp2 are born with apparently normal skeleton but suffer loss of BMD and spontaneous limb bone fracture in the adult life [6]. In addition, it appears that deletion of Bmp4 alone at the embryonic stage does not alter adult skeleton [13]. We observed that deletion of Bmp2 allele in adult mice caused no skeletal phenotype. However, when both Bmp2 and Bmp4 alleles were deleted in skeletally mature mice, we observed significant osteopenia suggesting that BMP signaling has a critical role in adult bone homeostasis. Bmp2c/c; Prx1-Cre mice were compromised in fracture healing [6] while in our case some bone regenerative response following bone injury was observed in KO mice, albeit significantly lesser than control mice. This difference in bone injury healing response between these two strains may be attributed to certain subtle defects in Bmp2c/c; Prx1-Cre mice caused by lack of optimal level of BMP signaling during embryonic development. Our study, taken together with available literature, further reveals that just like in the embryos, absence of either of Bmp2 or Bmp4 gene alone does not affect adult skeleton [13, 53] but when deleted together, results in the development of osteopenia reflected by compromised trabecular integrity and reduced vertebral compression strength.