Loss of Myostatin (GDF8) Function Increases Osteogenic Differentiation of Bone Marrow-derived Mesenchymal Stem Cells but the Osteogenic Effect is Ablated with Unloading

Overview

Journal Bone

Specialties Endocrinology
Orthopedics

Date 2007 Mar 27

PMID 17383950

Citations 84

Authors

M W Hamrick

X Shi

W Zhang

C Pennington

H Thakore

M Haque

B Kang

C M Isales

S Fulzele

K H Wenger

Affiliations

Soon will be listed here.

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.

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References

Wehling M, Cai B, Tidball J . Modulation of myostatin expression during modified muscle use. FASEB J. 2000; 14(1):103-10. DOI: 10.1096/fasebj.14.1.103. View

Hamrick M, Ding K, Pennington C, Chao Y, Wu Y, Howard B . Age-related loss of muscle mass and bone strength in mice is associated with a decline in physical activity and serum leptin. Bone. 2006; 39(4):845-53. DOI: 10.1016/j.bone.2006.04.011. View

Lalani R, Bhasin S, Byhower F, Tarnuzzer R, Grant M, Shen R . Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flight. J Endocrinol. 2000; 167(3):417-28. DOI: 10.1677/joe.0.1670417. View

Yarasheski K, Bhasin S, Sinha-Hikim I, Gonzalez-Cadavid N . Serum myostatin-immunoreactive protein is increased in 60-92 year old women and men with muscle wasting. J Nutr Health Aging. 2002; 6(5):343-8. View

Aparicio L, Jurkovic M, DeLullo J . Decreased bone density in ambulatory patients with duchenne muscular dystrophy. J Pediatr Orthop. 2002; 22(2):179-81. View

Qin Y, Kaplan T, Saldanha A, Rubin C . Fluid pressure gradients, arising from oscillations in intramedullary pressure, is correlated with the formation of bone and inhibition of intracortical porosity. J Biomech. 2003; 36(10):1427-37. DOI: 10.1016/s0021-9290(03)00127-1. View

Shuto T, Sarkar G, Bronk J, Matsui N, Bolander M . Osteoblasts express types I and II activin receptors during early intramembranous and endochondral bone formation. J Bone Miner Res. 1997; 12(3):403-11. DOI: 10.1359/jbmr.1997.12.3.403. View

Raitakari M, Nuutila P, Ruotsalainen U, Teras M, Eronen E, Laine H . Relationship between limb and muscle blood flow in man. J Physiol. 1996; 496 ( Pt 2):543-9. PMC: 1160897. DOI: 10.1113/jphysiol.1996.sp021705. View

Schonau E, Werhahn E, Schiedermaier U, Mokow E, Schiessl H, Scheidhauer K . Influence of muscle strength on bone strength during childhood and adolescence. Horm Res. 1996; 45 Suppl 1:63-6. DOI: 10.1159/000184834. View

10.

Rebbapragada A, Benchabane H, Wrana J, Celeste A, Attisano L . Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis. Mol Cell Biol. 2003; 23(20):7230-42. PMC: 230332. DOI: 10.1128/MCB.23.20.7230-7242.2003. View

11.

Parfitt A, Drezner M, Glorieux F, Kanis J, MALLUCHE H, Meunier P . Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987; 2(6):595-610. DOI: 10.1002/jbmr.5650020617. View

12.

Justesen J, Stenderup K, Ebbesen E, Mosekilde L, Steiniche T, Kassem M . Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology. 2001; 2(3):165-71. DOI: 10.1023/a:1011513223894. View

13.

Doyle F, Brown J, Lachance C . Relation between bone mass and muscle weight. Lancet. 1970; 1(7643):391-3. DOI: 10.1016/s0140-6736(70)91520-5. View

14.

McMahon C, Popovic L, Oldham J, Jeanplong F, Smith H, Kambadur R . Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls during hindlimb suspension. Am J Physiol Endocrinol Metab. 2003; 285(1):E82-7. DOI: 10.1152/ajpendo.00275.2002. View

15.

Bouxsein M, Lewis B, Charette S, Weinstein P, Marcus R . Muscle strength as a predictor of bone mineral density in young women. J Bone Miner Res. 1990; 5(6):589-95. DOI: 10.1002/jbmr.5650050608. View

16.

Funaba M, Ogawa K, Abe M . Expression and localization of activin receptors during endochondral bone development. Eur J Endocrinol. 2001; 144(1):63-71. DOI: 10.1530/eje.0.1440063. View

17.

Jilka R . Osteoblast progenitor fate and age-related bone loss. J Musculoskelet Neuronal Interact. 2005; 2(6):581-3. View

18.

Schuelke M, Wagner K, Stolz L, Hubner C, Riebel T, Komen W . Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004; 350(26):2682-8. DOI: 10.1056/NEJMoa040933. View

19.

Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung U, Kubota N . PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004; 113(6):846-55. PMC: 362117. DOI: 10.1172/JCI19900. View

20.

Hamalainen N, Pette D . The histochemical profiles of fast fiber types IIB, IID, and IIA in skeletal muscles of mouse, rat, and rabbit. J Histochem Cytochem. 1993; 41(5):733-43. DOI: 10.1177/41.5.8468455. View