Mutation in osteoactivin decreases bone formation in vivo and osteoblast differentiation in vitro.

Title

Mutation in osteoactivin decreases bone formation in vivo and osteoblast differentiation in vitro.

Creator

Abdelmagid Samir M; Belcher Joyce Y; Moussa Fouad M; Lababidi Suzanne L; Sondag Gregory R; Novak Kimberly M; Sanyurah Afif S; Frara Nagat A; Razmpour Roshanak; Del Carpio-Cano Fabiola E; Safadi Fayez F

Publisher

The American journal of pathology

Date

2014
2014-03

Description

We have previously identified osteoactivin (OA), encoded by Gpnmb, as an osteogenic factor that stimulates osteoblast differentiation in vitro. To elucidate the importance of OA in osteogenesis, we characterized the skeletal phenotype of a mouse model, DBA/2J (D2J) with a loss-of-function mutation in Gpnmb. Microtomography of D2J mice showed decreased trabecular mass, compared to that in wild-type mice [DBA/2J-Gpnmb(+)/SjJ (D2J/Gpnmb(+))]. Serum analysis showed decreases in OA and the bone-formation markers alkaline phosphatase and osteocalcin in D2J mice. Although D2J mice showed decreased osteoid and mineralization surfaces, their osteoblasts were increased in number, compared to D2J/Gpnmb(+) mice. We then examined the ability of D2J osteoblasts to differentiate in culture, where their differentiation and function were decreased, as evidenced by low alkaline phosphatase activity and matrix mineralization. Quantitative RT-PCR analyses confirmed the decreased expression of differentiation markers in D2J osteoblasts. In vitro, D2J osteoblasts proliferated and survived significantly less, compared to D2J/Gpnmb(+) osteoblasts. Next, we investigated whether mutant OA protein induces endoplasmic reticulum stress in D2J osteoblasts. Neither endoplasmic reticulum stress markers nor endoplasmic reticulum ultrastructure were altered in D2J osteoblasts. Finally, we assessed underlying mechanisms that might alter proliferation of D2J osteoblasts. Interestingly, TGF-beta receptors and Smad-2/3 phosphorylation were up-regulated in D2J osteoblasts, suggesting that OA contributes to TGF-beta signaling. These data confirm the anabolic role of OA in postnatal bone formation.

Subject

*Signal Transduction; Alkaline Phosphatase/metabolism; Animals; Apoptosis; Bone and Bones/metabolism/pathology; Cell Differentiation/genetics; Eye Proteins/*genetics; Inbred DBA; Male; Membrane Glycoproteins/*genetics; Mice; Mutation; Newborn; Osteoblasts/cytology/*physiology; Osteocalcin/*genetics; Osteogenesis/*genetics; Phenotype; Receptors; Transforming Growth Factor beta/metabolism

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

697–713

Issue

3

Volume

184

Citation

Abdelmagid Samir M; Belcher Joyce Y; Moussa Fouad M; Lababidi Suzanne L; Sondag Gregory R; Novak Kimberly M; Sanyurah Afif S; Frara Nagat A; Razmpour Roshanak; Del Carpio-Cano Fabiola E; Safadi Fayez F, “Mutation in osteoactivin decreases bone formation in vivo and osteoblast differentiation in vitro.,” NEOMED Bibliography Database, accessed March 19, 2024, https://neomed.omeka.net/items/show/3440.