Activins: Therapeutic Potential of Reproductive Regulators

Activins and inhibins, parts of the TGFβ superfamily with almost directly opposite biological effects, are best known to regulate reproductive physiology, impacting gonadal development, menstrual cycles, pregnancy maintenance, and immune modulation. They also play important roles in cell proliferation, differentiation, wound repair, and tissue and organ formation. Imbalances in activins and inhibins contribute to reproductive disorders like ovarian cancer, prostate cancer, and polycystic ovary syndrome, as well as other deseases like neurological disorders and musculoskeletal disorders. For example, Activin A, the most studied activin encoded by inhibin β A (INHBA), is shown to be implicated in inflammation and fibrosis. The multifaceted roles of activins and inhibins position them as promising targets for diagnosing, preventing, and treating various diseases. As a global leader in recombinant technology, Sino Biological is committed to provide premium recombinant proteins and corresponding antibodies, including activins (such as INHBA, INHBB, and INHBE) and activin receptors (such as ACVR2A and ACVR2B), aiming to advance activin-targeted drug development and offer novel solutions for various diseases.

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Physiological and Pathological Roles

Activins and inhibins, including Activin A, B, AB, C, and E, as well as inhibin A and B isoforms, belong to the TGFβ superfamily and regulate the follicle stimulating hormone (FSH) secretion and erythropoiesis (1,2). They play pivotal roles in reproductive biology, contributing to gonadal development, androgen synthesis, menstrual cycle regulation, implantation, pregnancy maintenance, and immune modulation. Additionally, They are involved in several biological processes including cell proliferation, differentiation, wound repair, and tissue and organ formation (3). Pathologically, imbalances in activin and inhibin levels link to disorders such as ovarian cancer, prostate cancer, polycystic ovary syndrome, and gestational complications (4,5). Beyond reproduction, they feature in diverse conditions, from cancers (prostate, breast, lung) to neurological disorders (5–9). As the most studied activin, activin A, encoded by INHBA, is a homodimer of two inhibin β A subunits. Activin A binds to the type II activin receptors (ACVR2A, ACVR2B) and then recruits and phosphorylates the type I activin receptor (ACVR1B), which signals through the SMAD2/3 proteins to regulate inflammation, fibrosis, and tumorigenesis (8,10). The versatile nature of activins and inhibins positions them as promising targets for diagnosing, preventing, and treating a spectrum of diseases.

Bench to Bedside

Activins or inhibins are not only significant for fertility and fecundity, but also affect cell proliferation and differentiation, muscle, fat and bone mass regulation. Due to their association with various conditions, targeted therapeutic strategies against them is being widely discussed and applied in various diseases5. The journey from bench to bedside is ongoing, with promising research exploring the therapeutic potential of activins. ACVR2A is a primary target in treating blood disorders, tumors, and musculoskeletal diseases, while ACVR2B is explored for conditions like muscle atrophy, neurological disorders, cachexia, and obesity. INHBA is also widely studied for treating skeletal diseases, malignant tumors, and cachexia, among other conditions (Table 1).

Application in Research

As more researchers recognize the involvement of activin and inhibin in blood disorders, neurological disorders, skeletal diseases, tumors, and more, an increasing number of studies targeting activin and inhibin in various diseases are gradually unfolding. Martin L. and colleagues developed a novel method for detection of activin receptor type II in human blood using recombinant human ACVR2A-Fc (Cat#: 10257-H02H, Sino Biological) and ACVR2B-Fc (Cat#: 10229-H02H, Sino Biological) as positive controls, which could help in the development of anemia drugs (13) (Figure 2). Shan Y. and colleagues induced differentiation of blood cells in presence of BMP-4, Activin A (Cat#: 10429-HNAH, Sino Biological), VEGF (Sino Biological), and FGF2 (Cat#: 10014-HNAE, Sino Biological) to study the role of polycomb repressive complex 2 (PRC2) in pluripotency of primed ESCs14 (Figure 3). Reader and colleagues demonstrated that Activin B can be used as a potential biomarker for distinguishing aggressive from indolent prostate cancer and identified that overexpression of Activin B (Cat#: HG10814-NF, Sino Biological) in PC3 cells resulted in a robust increase in cell growth and migration (Figure 4)(10). Reichel and colleagues reported a novel approach to detecting Sotatercept (ACE-011, ACVR2A-Fc) in human serum, where anti-human ACVR2A antibodies (Sino Biological) were used to recognize Sotatecept (Figure 5) (15).

References

1. Namwanje, M. & Brown, C. W. Activins and inhibins: Roles in development, physiology, and disease. Cold Spring Harb Perspect Biol 8, (2016).

2. Makanji, Y. et al. Inhibin at 90: From discovery to clinical application, a historical review. Endocrine Reviews vol. 35 747–794 Preprint at https://doi.org/10.1210/er.2014-1003 (2014).

3. Appiah Adu-Gyamfi, E. et al. Activin and inhibin signaling: From regulation of physiology to involvement in the pathology of the female reproductive system. Cytokine vol. 133 Preprint at https://doi.org/10.1016/j.cyto.2020.155105 (2020).

4. Wijayarathna, R. & de Kretser, D. M. Activins in reproductive biology and beyond. Hum Reprod Update 22, 342–357 (2016).

5. Hagg, A., O’Shea, E., Harrison, C. A. & Walton, K. L. Targeting activins and inhibins to treat reproductive disorders and cancer cachexia. J Endocrinol 258, (2023).

6. Tsuchida, K. et al. Activin signaling as an emerging target for therapeutic interventions. Cell Communication and Signaling vol. 7 Preprint at https://doi.org/10.1186/1478-811X-7-15 (2009).

7. Link, A. S., Zheng, F. & Alzheimer, C. Activin signaling in the pathogenesis and therapy of neuropsychiatric diseases. Frontiers in Molecular Neuroscience vol. 9 Preprint at https://doi.org/10.3389/fnmol.2016.00032 (2016).

8. Li, F., Long, Y., Yu, X., Tong, Y. & Gong, L. Different Immunoregulation Roles of Activin A Compared With TGF-β. Frontiers in Immunology vol. 13 Preprint at https://doi.org/10.3389/fimmu.2022.921366 (2022).

9. Staudacher, J. J. et al. Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas. BMC Cancer 22, (2022).

10. Reader, K. L. et al. Activin B and Activin C Have Opposing Effects on Prostate Cancer Progression and Cell Growth. Cancers (Basel) 15, (2023).

11. Bloise, E. et al. Activin A in Mammalian Physiology. Physiol Rev 99, 739–780 (2019).

12. Appiah Adu-Gyamfi, E. et al. Activin and inhibin signaling: From regulation of physiology to involvement in the pathology of the female reproductive system. Cytokine 133, 155105 (2020).

13. Martin, L., Zouhiri, N., Audran, M. & Marchand, A. A validated, sensitive electrophoretic method for the detection of activin receptor type II‐Fc fusion proteins in human blood. Drug Test Anal 10, 1226–1236 (2018).

14. Shan, Y. et al. PRC2 specifies ectoderm lineages and maintains pluripotency in primed but not na?ve ESCs. Nat Commun 8, 672 (2017).

15. Reichel, C., Farmer, L., Gmeiner, G., Walpurgis, K. & Thevis, M. Detection of Sotatercept (ACE‐011) in human serum by SAR‐PAGE and western single blotting. Drug Test Anal 10, 927–937 (2018).