Effects of second‐generation tyrosine kinase inhibitors towards osteogenic differentiation of human mesenchymal cells of healthy donors

Abstract

The BCR-ABL inhibitor imatinib is a standard first-line therapy for patients with chronic myeloid leukemia. However, it has been demonstrated that this long-term treatment is associated with altered bone metabolism. The mechanisms of this effect are not fully understood, but an inhibition of the platelet-derived growth factor receptor (PDGF-R) β axis has been suspected on the basis of some in vitro findings. We evaluated the osteoblastic differentiation of mesenchymal stem cells derived from bone marrow (hBM-MSCs) after in vitro treatment with dasatinib, nilotinib or bosutinib. Human bone marrow mesenchymal stem cells were induced to differentiate in osteoblastic cells by treatment with osteogenic medium with or without dasatinib, nilotinib or bosutinib. We found that the addition of dasatinib, and to a greater extend nilotinib, induced expression of osteogenic mRNA markers as compared with cultures with standard medium or osteogenic medium only. However, treatment with bosutinib did not induce an increase of osteogenic markers. In conclusion, we show that besides imatinib, other tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib, but not bosutinib, increase osteogenic markers in hBM-MSCs. Because bosutinib differs from the other TKIs because of its low affinity to other kinases such as PDGF-R, these experiments suggest that inhibition of PDGF-R may be involved in the induction of osteoblastogenesis by TKIs.

SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation

“…In this perspective, we [21] and others [22-25] have demonstrated that in CML patients treated with IM there is a transient increase in bone-formation markers that could be linked to inhibition of PDGFR signaling. We have also demonstrated that also NI induced osteoblastogenesis in vitro, probably triggering the same IM targets [26]. Therefore the increase of SPARC induced by TKIs could be related to the well documented modification of the bone metabolism observed in IM treated patients.…”

The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

“…However, the reported findings significantly disagreed [56]–[58]. Jonsson and colleagues showed that dasatinib inhibits the proliferation of MSC and their bone morphogenetic protein-dependent osteoblastic differentiation [56].…”

Chronic myeloid leukemia: Second‐line drugs of choice

“…Similarly, these findings could be also documented during treatment with other TKIs such as nilotinib and dasatinib [47,48]. Some reports also described cases of worsening of hypothyroidism or thyroid abnormalities during Imatinib and 2 nd generation TKIs, which needed increased dosages of hormone supplementation [49].…”