A follistatin‐based molecule increases muscle and bone mass without affecting the red blood cell count in mice

Abstract

Inhibitors of the activin receptor signaling pathway (IASPs) have become candidate therapeutics for sarcopenia and bone remodeling disorders because of their ability to increase muscle and bone mass. However, IASPs utilizing activin type IIA and IIB receptors are also potent stimulators of erythropoiesis, a feature that may restrict their usage to anemic patients because of increased risk of venous thromboembolism. Based on the endogenous TGF‐β superfamily antagonist follistatin (FST), a molecule in the IASP class, FSTΔHBS‐mFc, was generated and tested in both ovariectomized and naive BALB/c and C57BL/6 mice. In ovariectomized mice, FSTΔHBS‐Fc therapy dose‐dependently increased cancellous bone mass up to 42% and improved bone microstructural indices. For the highest dosage of FSTΔHBS‐mFc (30 mg/kg, 2 times/wk), the increase in cancellous bone mass was similar to that observed with parathyroid hormone therapy (1–34,80 µg/kg, 5 times/wk). Musculus quadriceps femoris mass dose‐dependently increased up to 21% in ovariectomized mice. In both ovariectomized and naive mice, FSTΔHBS‐mFc therapy did not influence red blood cell count or hematocrit or hemoglobin levels. If the results are reproduced, a human FSTΔHBS‐mFc version could be applicable in patients with musculoskeletal conditions irrespective of hematocrit status.—Lodberg, A., van der Eerden, B. C. J., Boers‐Sijmons, B., Thomsen, J. S., Brüel, A., van Leeuwen, J. P. T. M., Eijken, M. A follistatin‐based molecule increases muscle and bone mass without affecting the red blood cell count in mice. FASEB J. 33, 6001–6010 (2019). http://www.fasebj.org

Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma

“…The ability of FST ΔHBS ‐hFc to increase body weight in the face of progressing osteosarcoma is, therefore, an interesting feature and it is likely attributable to skeletal muscle preservation as has been noted in other cancer types with some IASPs 40,41 . ActRIIA‐mFc did not significantly alter body weight and this difference between the IASPs may likely be attributed to ActRIIA‐mFc not blocking myostatin as strongly as FST ΔHBS ‐hFc 16 …”

“…The construction and expression and purification procedures of ActRIIA‐mFc and FST ΔHBS ‐hFc were recently described in detail 16 . Briefly, ActRIIA‐mFc represents a fusion protein of the human ActRIIA ectodomain fused to the Fc region of murine IgG2a, including a TGGG linker.…”

“…Activin A and GDF11 initiate signaling via membrane proteins known as activin type II receptors (ActRIIs; ActRIIA and ActRIIB). Collectively, compounds that prevent transduction through these receptors may be referred to as inhibitors of the activin receptor signaling pathway (IASPs) 6,16 …”

“…In this study, we explored inhibition of the activin receptor signaling pathway as a therapy for osteosarcoma. Two types of IASPs were tested: 1) a soluble activin type IIA decoy receptor (ActRIIA‐mFc), 4 and 2) a modified variant of the native antagonist, follistatin (FST), (FST ΔHBS ‐hFc) 16 . The two IASPs were tested alone or in combination with bisphosphonate in an intratibial human xenograft osteosarcoma mouse model.…”

“…Collectively, compounds that prevent transduction through these receptors may be referred to as inhibitors of the activin receptor signaling pathway (IASPs). 6,16 Bisphosphonates are chemically stable derivatives of inorganic pyrophosphate that have a natural predilection for hydroxyapatite crystals. 17 During bone remodeling, bisphosphonate is absorbed by the osteoclast and incorporated into the cell's adenosine triphosphate production.…”