Loss of myostatin (GDF8) function increases osteogenic differentiation of bone marrow-derived mesenchymal stem cells but the osteogenic effect is ablated with unloading

Abstract

Myostatin (GDF8) is a negative regulator of skeletal muscle growth and mice lacking myostatin show a significant increase in muscle mass and bone density compared to normal mice. In order to further define the role of myostatin in regulating bone mass we sought to determine if loss of myostatin function significantly altered the potential for osteogenic differentiation in bone marrow-derived mesenchymal stem cells in vitro and in vivo. We first examined expression of the myostatin receptor, the type IIB activin receptor (AcvrIIB), in bone marrow-derived mesenchymal stem cells (BMSCs) isolated from mouse long bones. This receptor was found to be expressed at high levels in BMSCs, and we were also able to detect AcvrIIB protein in BMSCs in situ using immunofluorescence. BMSCs isolated from myostatin-deficient mice showed increased osteogenic differentiation compared to wild-type mice; however, treatment of BMSCs from myostatin-deficient mice with recombinant myostatin did not attenuate the osteogenic differentiation of these cells. Loading of BMSCs in vitro increased the expression of osteogenic factors such as BMP-2 and IGF-1, but treatment of BMSCs with recombinant myostatin was found to decrease the expression of these factors. We investigated the effects of myostatin loss-of-function on the differentiation of BMSCs in vivo using hindlimb unloading (7-day tail suspension). Unloading caused a greater increase in marrow adipocyte number, and a greater decrease in osteoblast number, in myostatin-deficient mice than in normal mice. These data suggest that the increased osteogenic differentiation of BMSCs from mice lacking myostatin is load-dependent, and that myostatin may alter the mechanosensitivity of BMSCs by suppressing the expression of osteogenic factors during mechanical stimulation. Furthermore, although myostatin deficiency increases muscle mass and bone strength, it does not prevent muscle and bone catabolism with unloading.

Serum myostatin levels are negatively associated with abdominal aortic calcification in older men: the STRAMBO study

“…So far, myostatin has not been implicated in mineral homeostasis crucial for the pathophysiology of vascular calcification. However, bone marrow-derived MSCs obtained from myostatinnull mice exhibited increased osteogenic differentiation compared with cells from wild-type mice (13), and myostatin expression increased transiently after fracture (47). Myostatin treatment reduced type II collagen synthesis and expression of Sox9 mRNA, a transcription factor for chondrocyte differentiation (48).…”

“…In addition to the above factors, AAC and myostatin secretion may share other mechanisms. In myostatin deficient mice, mesenchymal stem cells (MSCs) undergo increased osteogenic differentiation (13). Interestingly, the number of circulating osteoprogenitor cells was higher in postmenopausal osteoporotic women with AAC compared with women without AAC (14).…”

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta

“…This could also account for the evidence of increased serum osteocalcin in 4-mo-old offspring of Mstn tm1Sjl/+ dams. Muscle, bone, and fat are derived from the same precursor, mesenchymal stem cells (25). Addition of myostatin increases commitment of the mesenchymal stem cell [C3H 10T(1/2)] to an adipogenic fate, and mesenchymal stem cells from myostatin-deficient mice show increased osteogenic potential in vitro (25).…”

“…Muscle, bone, and fat are derived from the same precursor, mesenchymal stem cells (25). Addition of myostatin increases commitment of the mesenchymal stem cell [C3H 10T(1/2)] to an adipogenic fate, and mesenchymal stem cells from myostatin-deficient mice show increased osteogenic potential in vitro (25). However, as maternal myostatin did not enter the fetal circulation and fetal size was increased overall, an indirect action of maternal myostatin on fetal bone is likely.…”

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

“…Interestingly, a soluble form of activin receptor type IIA, which acts as an activin antagonist, was shown to increase bone formation, bone mass, and strength in OVX mice and non-human primates (82,83). Furthermore, mice lacking GDF8, which binds to activin receptor type IIB and antagonizes osteogenic differentiation, show increased bone mineral density, suggesting that the development of GDF8 antagonists may promote bone formation in vivo (84,85). Other growth factors may be candidates for use as bone anabolic factors.…”