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Abstract Number: 69

The Effect of Myostatin Inhibition on Bone Loss in Murine Osteoporosis Models

Tomoyuki Mukai1, Takafumi Mito1, Shunichi Fujita1, Shoko Kodama1, Akiko Nagasu1, Teruki Sone2, Shinichiro Nishimatsu3, Yutaka Ohsawa4, Yoshihide Sunada4 and Yoshitaka Morita1, 1Department of Rheumatology, Kawasaki Medical School, Kurashiki, Okayama, Japan, 2Department of Nuclear Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan, 3Department of Natural Sciences, Kawasaki Medical School, Kurashiki, Okayama, Japan, 4Department of Neurology, Kawasaki Medical School, Kurashiki, Okayama, Japan

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Animal models, bone biology, Musculoskeletal, osteoclasts and osteoporosis

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Session Information

Date: Sunday, November 5, 2017

Title: Biology and Pathology of Bone and Joint Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Myostatin, also called as growth differentiation factor-8 (GDF-8), is a secreted member of TGF-β superfamily. Myostatin is a negative regulator of skeletal muscle mass as shown by increased muscle mass in myostatin-deficient mice. A recent study reported the regulatory role of myostatin on bone metabolism (Dankbar B, et al. Nat Med 2015). The study showed that myostatin directly regulates osteoclastogenesis and its inhibition reduces inflammatory joint destruction in murine arthritis models. In contrast to this, another group reported that myostatin inhibition by the administration of anti-myostatin antibody did not affect bone mass of femur and vertebra in wild-type mice (Bialek P, et al. Bone 2014). Therefore, it is still controversial whether myostatin inhibition could regulate bone mass. Here, we report the effect of genetic inhibition of myostatin on bone loss in murine osteoporosis models.

Methods:

We used mutant myostatin transgenic (MstnPro) mice, in which myostatin prodomain, an endogenous myostatin suppressor, is excessively expressed and subsequently inhibits myostatin activity. For a RANKL-induced osteoporosis model, 1 mg/kg of RANKL was injected intraperitoneally at day 0 and 1, and the sera and bones were collected at day 2. For a tail-suspension unloading model, the tails of mice were suspended for 2 weeks. At the end of the period, the sera and bones were collected. Serum TRAP5b and P1NP levels were measured by ELISA. Bone properties of vertebra and tibia were determined by micro-CT. For cell culture experiments, bone marrow cells were isolated from long bones of wild-type (WT) and MstnPro mice. Bone marrow-derived macrophages (BMMs) were treated with RANKL, and then osteoclast differentiation and function were determined by TRAP staining and resorption assay.

Results:

MstnPro mice exhibited increased muscle mass similarly to the previously reported myostatin null mice. RANKL injection induced severe bone loss in MstnPro mice to the similar extent to that seen in WT mice (WT: 31.0 ± 10.0% reduction, MstnPro: 42.8 ± 9.6% reduction compared to control mice of each genotype). Serum TRAP5b and P1NP levels were also comparable between RANKL-treated WT and MstnPro mice. In the tail-suspension model, genetic inhibition of myostatin did not also prevent bone loss. In WT BMMs culture, myostatin stimulation slightly enhanced RANKL-induced osteoclastogenesis. Osteoclast formation and resorbed area in response to RANKL were comparable between WT and MstnPro BMMs.

Conclusion:

Genetic inhibition of myostatin did not alleviate bone loss in the osteoporosis models we tested. The role of myostatin inhibition might vary in different pathological conditions (e.g. inflammatory or non-inflammatory conditions). Further research will be required to clarify the clinical implications of myostatin inhibition in various disease settings.


Disclosure: T. Mukai, Takeda Pharmaceutical Co., Ltd., 2,Pfizer Japan Inc., 2,Mitsubishi Tanabe Pharma Co., 2,Chugai Pharmaceutical Co., Ltd., 2,AbbVie GK, 2,TEIJIN Pharma Ltd., 2,Astellas Pharma Inc., 2,Japan Blood Products Organization, 2,Shionogi & Co., Ltd., 2,Actelion Pharmaceuticals Japan Ltd., 2,Eli Lilly Japan K.K., 2,DAIICHI SANKYO Co., Ltd., 2,UCB Japan Co. Ltd., 2; T. Mito, None; S. Fujita, None; S. Kodama, None; A. Nagasu, None; T. Sone, None; S. Nishimatsu, None; Y. Ohsawa, None; Y. Sunada, None; Y. Morita, Takeda Pharmaceutical Co., Ltd., 2,Pfizer Japan Inc., 2,Mitsubishi Tanabe Pharma Co., 2,Chugai Pharmaceutical Co., Ltd., 2,AbbVie GK, 2,TEIJIN Pharma Ltd., 2,Astellas Pharma Inc., 2,Japan Blood Products Organization, 2,Shionogi & Co., Ltd., 2,Actelion Pharmaceuticals Japan Ltd., 2,Eli Lilly Japan K.K., 2,DAIICHI SANKYO Co., Ltd., 2.

To cite this abstract in AMA style:

Mukai T, Mito T, Fujita S, Kodama S, Nagasu A, Sone T, Nishimatsu S, Ohsawa Y, Sunada Y, Morita Y. The Effect of Myostatin Inhibition on Bone Loss in Murine Osteoporosis Models [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/the-effect-of-myostatin-inhibition-on-bone-loss-in-murine-osteoporosis-models/. Accessed .
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