Methotrexate chemotherapy–induced damages in bone marrow sinusoids: An in vivo and in vitro study

Abstract

Chemotherapeutic agents are very well evident extrinsic stimuli for causing damage to endothelial cells. Methotrexate is an antimetabolite commonly used to treat solid tumours and paediatric cancers. However, studies on the effect(s) of methotrexate on bone marrow microvascular system are inadequate. In the current study, we observed a significant bone marrow microvascular dilation following methotrexate therapy in rats, accompanied by apoptosis induction in bone marrow sinusoidal endothelial cells, and followed by recovery of bone marrow sinusoids associated with increased proliferation of remaining bone marrow sinusoidal endothelial cells. Our in vitro studies revealed that methotrexate is cytotoxic for cultured sinusoidal endothelial cells and can also induce apoptosis which is associated with upregulation of expression ratio of Bax and Bcl-2 genes and Bax/Bcl-2 expression ratio. Furthermore, it was shown that methotrexate can negatively affect proliferation of cultured sinusoidal endothelial cells and also inhibit their abilities of migration and formation of microvessel like tubes. The data from this study indicates that methotrexate can cause significant bone marrow sinusoidal endothelium damage in vivo and induce apoptosis and inhibit proliferation, migration and tube-forming abilities of sinusoidal endothelial cells in vitro. K E Y W O R D S angiogenesis, apoptosis, bone marrow sinusoidal endothelial cells, bone marrow sinusoids, methotrexate J Cell Biochem. 2019;120:3220-3231. wileyonlinelibrary.com/journal/jcb

Retracted: Release of CXCL12 From Apoptotic Skeletal Cells Contributes to Bone Growth Defects Following Dexamethasone Therapy in Rats

“…A – E ), suggesting that changes in the secondary spongiosa trabecular bone are consistent with those in the amounts of primary spongiosa, from which the secondary spongiosa are derived. In addition, accumulated evidence suggests that cancer chemotherapy, including Dex treatment, could adversely impact bone marrow microvasculature (sinusoidal endothelium), and that CXCL12/CXCR4 signaling has the potential to preserve microvascular integrity . However, apart from the insignificant decrease in sinusoidal diameter in anti‐CXCL12 antibody supplementation groups in comparison with control IgG supplementation groups, no differences were observed among the four treatment groups (Fig.…”

“…To examine treatment effects on the histological structures of the growth plate cartilage and bone, histomorphometric analyses were performed on H&E‐ stained paraffin sections. Growth plate thickness and primary spongiosa heights as well as bone volume fraction (bone volume/total tissue volume [BV/TV%]), trabecular structural parameters (trabecular number, thickness, and spacing), adipocyte densities and sinusoidal diameters within bone marrow of secondary spongiosa in metaphysis were measured as described . In addition, staining of tartrate‐resistant acid phosphatase (TRAP) was conducted to evaluate the treatment effects on recruitment of cartilage‐resorbing chondroclasts and bone‐resorbing osteoclasts as described …”

Retracted: Icariin attenuates methotrexate chemotherapy‐induced bone marrow microvascular damage and bone loss in rats

“…Adipocytes at the lowest region of secondary spongiosa were identified by their typical size, shape, and location and the number of adipocytes/mm 2 marrow area was also quantified as described before (Georgiou et al, ). In addition, the diameters of BM sinusoids in the secondary spongiosa were measured as described (Hassanshahi et al, ). Sinusoids were defined morphologically as thin monolayered walled with having an irregular shape, and often gaping vessels which may contain red blood cells and/or hematopoietic elements (Ewalt & Gratzinger, ).…”

Bone marrow sinusoidal endothelium as a facilitator/regulator of cell egress from the bone marrow

“…SECs are also found in other tissues such as liver (Samson, 2013) and spleen (Huang et al, 2014). By delivering oxygen, nutrients, cells, and growth factors, the BM microvascular system plays a substantial role in orchestrating diverse physiological functions including haematopoiesis, bone formation and bone remodelling (Hassanshahi et al, 2018a;Hassanshahi et al, 2018b). Moreover, the BM microvascular system possesses a strong regeneration-enabling potency, for example for BM haematopoiesis by providing tissue/organ-specific "angiocrine factors" (Rafii et al, 2016).…”