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 (Mstn^Pro) 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 Mstn^Pro 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:

Mstn^Pro mice exhibited increased muscle mass similarly to the previously reported myostatin null mice. RANKL injection induced severe bone loss in Mstn^Pro mice to the similar extent to that seen in WT mice (WT: 31.0 ± 10.0% reduction, Mstn^Pro: 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 Mstn^Pro 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 Mstn^Pro 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-myostatin-inhibition-on-bone-loss-in-murine-osteoporosis-models/