Activins are typical members of the transforming growth factor beta superfamily in that they contain a conserved cysteine knot motif and are secreted as homo- or heterodimers of related beta-subunits. Activins seem to be implicated in the regulation of erythropoiesis and bone metabolism. Many studies have documented erythropoietic effects of activin-A in transformed cell lines or other in vitro models; however, there is a paucity of functional data regarding hematopoietic roles of activin-A in vivo. Regarding bone remodeling, activin A is produced by osteoblasts, osteoclasts, and bone marrow cells, and there is agreement that activin-A promotes osteoclast development in vitro; however, the effect of activin-A on osteoblast development in vitro varies dramatically depending on experimental conditions. It is of interest that activin-A antagonists (i.e. sotatercept) have increased hemoglobin and bone mineral density (BMD) in patients with multiple myeloma who receive chemotherapy, giving the rationale for their use in other hematological disorders with anemia, like myelodysplastic syndromes.
Thalassemia is characterized by ineffective hemopoiesis, while osteopenia or osteoporosis is found in the vast majority of patients due to several reasons including bone marrow expansion and endocrine disorders. The role of activin-A has never been evaluated in hemoglobinopathies. The aim of this study was to examine the role of activin-A in different hemoglobinopathies in an attempt to explore if there is any rationale for the use of activin-A antagonists in this cohort of patients. Therefore, we measured circulating levels of activin-A in 227 patients with hemoglobinopathies: 58 patients had beta-thalassemia major (TM), 43 had beta-thalassemia intermedia (TI), 109 had double heterozygous sickle-cell/beta-thalassemia (HbS/beta-thal) and 17 had homozygous sickle cell disease (SCD) and we explored possible correlations with clinical and laboratory data including bone mineral density (BMD). Activin-A was also measured in the serum of 17, age- and gender-matched, healthy individuals who served as controls. For the evaluation of activin-A, we used an ELISA methodology (Quantikine, R&D Systems, Minneapolis, MN, USA). BMD of the lumbar spine (L1-L4), femoral neck (FN) and distal radius (R) was determined using Dual-energy X-ray absorptiometry (DXA) at the time of activin-A measurement.
Patients with TM (mean±SD: 481±213 pg/ml) and HbS/beta-thal (459±181 pg/ml) had elevated circulating activin-A compared to controls (361±87 pg/ml; p=0.041 and p=0.038, respectively). Furthermore, TM patients had higher activin-A levels compared to patients with TI (427±509 pg/ml, p=0.002), while circulating activin-A levels did not differ between TI patients and controls (p=0.811) or between SCD patients (422±132 pg/ml) and controls (p=0.202). In patients with TM, high circulating activin-A showed strong correlations with markers of hemolysis, such as elevated reticulocyte counts (r=0.406, p=0.011) and high lactate dehydrogenase (LDH; r=0.397, p=0.024). Similarly, in HbS/beta-thal patients, activin-A showed positive correlations with indirect bilirubin (r=0.399, p<0.001), ferritin (r=0.270, p=0.005) and LDH (r=0.194, p=0.044). Regarding BMD, osteoporosis (according to the WHO definition based on DXA data) was present in 45% of patients with TM, in 40% of patients with TI, in 33% of SCD patients and in 25% of patients with HbS/beta-thal. High activin-A correlated with low Z-score of L1-L4 BMD in TI patients (r=0.615, p<0.01) and low Z-score of FN-BMD in TM patients (r=0.456, p<0.01).
Our data suggest that activin-A is elevated in the serum of patients with TM and HbS/beta-thal and correlates with markers of hemolysis and low BMD. These observations in addition to previously published data that single nucleotide polymorphisms in activin-A receptor type II-like 1 independently contributes to pulmonary hypertension in SCD support a role of activin-A in the biology of these hemoglobinopathies, making activin-A an attractive agent for the development of novel therapies. The strong correlation of high activin-A with bone loss also supports the use of activin-A antagonists in patients with thalassemia and osteopenia or osteoporosis.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.