Polycythemia is a disease characterized by an increased number of mature erythrocytes in the circulation causing enhanced blood viscosity and thereby augmenting the clinical risk of thrombosis, cardiac infarction and stroke. Primary polycythemia (polycythemia rubra vera or Vaquez’ disease) is a chronic myeloproliferative disorder of the bone marrow marked by enhanced number of erythrocytes, leukocytes and thrombocytes and low levels of erythropoietin (Epo). In contrast, secondary polycythemia, frequently induced by hypoxic conditions such as heavy smoking, chronic obstructive pulmonary diseases and living at high altitude, is caused by enhanced Epo concentrations with selective increase of the erythrocyte number triggered by hypoxia-inducible factor-2α (HIF-2α).
Epo, a protein of 30 kDa, is in adults mainly produced in the kidney by interstitial cells and to some degree in the liver by hepatocytes. Epo is a crucial regulator of erythropoiesis that stimulates the proliferation and terminal differentiation of erythroid precursor cells. Therefore, administration of recombinant Epo has become the standard treatment for anemia in chronic kidney disease.
There is growing evidence that components of the extracellular matrix (ECM) have not only a structural function within the ECM but may also act in their soluble form as signaling molecules. Biglycan, a class I small leucine-rich proteoglycan, is proteolytically released from the ECM upon tissue stress or injury as a soluble molecule thereby acting as a danger signal. As an endogenous ligand of the innate immune receptors such as Toll-like receptor (TLR)-2 and -4, soluble biglycan promotes inflammation via its ability to evoke the expression of proinflammatory cytokines and chemokines.
Prof. Liliana Schaefer and scientists from the Institut für allgemeine Pharmakologie und Toxikologie at the Klinikum of the Goethe-Universität Frankfurt generated a transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGNTg). As a consequence biglycan was constantly released into the blood stream. BGNTg mice were systematically phenotyped in the German Mouse Clinic. The mice harbored an increase in mature circulating erythrocytes, elevated hemoglobin concentrations, hematocrit values and enhanced total iron binding capacity – clinical signs of polycythemia.
Further experiments showed that i) BGNTg mutants had enhanced Epo mRNA expression in the liver and kidney, while elevated Epo protein levels were found in liver, kidney and blood. ii) the transgenic animals had an abundance of HIF-2α protein in the liver and kidney. The transient overexpression of circulating biglycan in mice deficient in various Toll-like receptors (TLRs) revealed a novel function of biglycan. It promotes Epo synthesis by a selective interaction with TLR2. This process works presumably in an oxygen-independent manner, ultimately giving rise to secondary polycythemia.
Frey H & Moreth K, Hsieh LT, Zeng-Brouwers J, Rathkolb B, Fuchs H, Gailus-Durner V, Iozzo RV, de Angelis MH, Schaefer L. A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia. Glycoconj J. 2016 Sep 6. 2016