Conditional Deletion of Gremlin Causes a Transient Increase in Bone Formation and Bone Mass

Abstract

Gremlin is a glycoprotein that binds bone morphogenetic proteins (BMPs) 2, 4, and 7, antagonizing their actions. Gremlin opposes BMP effects on osteoblastic differentiation and function in vitro and in vivo, and its overexpression causes osteopenia. To define the function of gremlin in the skeleton, we generated gremlin 1 (grem1) conditional null mice by mating mice where grem1 was flanked by lox P sequences with mice expressing the Cre recombinase under the control of the osteocalcin promoter. grem1 null male mice displayed increased trabecular bone volume due to enhanced osteoblastic activity, because mineral apposition and bone formation rates were increased. Osteoblast number and bone resorption were not altered. Marrow stromal cells from grem1 conditional null mice expressed higher levels of alkaline phosphatase activity. Gremlin downregulation by RNA interference in ST-2 stromal and MC3T3 osteoblastic cells increased the BMP-2 stimulatory effect on alkaline phosphatase activity, on Smad 1/5/8 phosphorylation, and on the transactivation of the BMP/Smad reporter construct 12؋SBE-Oc-pGL3. Gremlin down-regulation also enhanced osteocalcin and Runx-2 expression, Wnt 3a signaling, and activity in ST-2 cells. In conclusion, deletion of grem1 in the bone microenvironment results in sensitization of BMP signaling and activity and enhanced bone formation in vivo.

A Lox/CHOP‐10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

“…BMPs, in combination with Wnt, induce MSCs to commit to osteoblastic lineage and enhance the pool and function of mature osteoblasts. Accordingly, BMP antagonists like Gremlin bind and suppress BMP signalling and activity in osteoblastic lineage cells, which tempers Wnt signalling,49 whereas deletion or down‐regulation of Gremlin sensitizes osteoblastic cells to the actions of BMP and Wnt 50. Our data show that Wnt/β‐catenin signalling is activated to stimulate BMP4‐induced osteogenesis by Lox inhibition and CHOP‐10 overexpression (Figures 3 and S4).…”

Activation of the ERK pathway in osteoblastic cells, role of gremlin and BMP‐2

“…Targeted overexpression of gremlin in the murine bone environment leads to osteopenia [Gazzerro et al, 2005], whereas the conditional deletion of grem1 in bone tissue causes a transient increase in bone formation and trabecular bone volume [Gazzerro et al, 2007]. Overexpression of gremlin in skeletal cells opposes BMP activity, whereas, downregulation of gremlin expression by RNA interference sensitizes osteoblasts to BMP signaling and activity [Gazzerro et al, 2007]. These observations suggest that the effects of gremlin can be explained by its ability to bind and oppose BMP activity.…”

“…In addition, gremlin is expressed by stromal cells surrounding certain neoplasms [Sneddon et al, 2006], where it is considered to play a role in cell survival and possibly tumorigenesis [Topol et al, 1997]. Targeted overexpression of gremlin in the murine bone environment leads to osteopenia [Gazzerro et al, 2005], whereas the conditional deletion of grem1 in bone tissue causes a transient increase in bone formation and trabecular bone volume [Gazzerro et al, 2007]. Overexpression of gremlin in skeletal cells opposes BMP activity, whereas, downregulation of gremlin expression by RNA interference sensitizes osteoblasts to BMP signaling and activity [Gazzerro et al, 2007].…”

Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis

“…166 Similarly, deletion of gremlin gene resulted in sensitization of BMP signaling and activity and in enhancement of bone formation in mice. 167 …”