Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease.

Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S.

Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice.

We have investigated the effect of long-term glucocorticoid (GC) administration on bone turnover in two frequently used mouse strains; C57BL/6J and CD1, in order to assess the influence of their genetic background on GC-induced osteoporosis (GIO). GIO was induced in 12 weeks old female C57BL/6J and CD1 mice by subcutaneous insertion of long-term release prednisolone or placebo pellets. Biomechanical properties as assessed by three point bent testing revealed that femoral elasticity and strength significantly decreased in CD1 mice receiving GC, whereas C57BL/6J mice showed no differences between placebo and prednisolone treatment.

Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.

The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low-dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model.

Effect of glycosphingolipids on osteoclastogenesis and osteolytic bone diseases.

Alterations in glycosphingolipid (GSL) production results in lysosomal storage disorders associated with neurodegenerative changes. In Gaucher's disease, the patients also develop osteoporosis that is ameliorated upon treatment for the underlying defect in GSL metabolism. The role of GSLs in osteoclast and osteoblast formation is discussed here as well as the potential therapeutic uses of already approved drugs that limit GSL production in bone loss disorders such as multiple myeloma and periodontal disease.

Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation.

A major therapeutic challenge is how to replace bone once it is lost. Bone loss is a characteristic of chronic inflammatory and degenerative diseases such as rheumatoid arthritis and osteoporosis. Cells and cytokines of the immune system are known to regulate bone turnover by controlling the differentiation and activity of osteoclasts, the bone resorbing cells.

Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo.

Osteoblasts play a crucial role in the hematopoietic stem cell (HSC) niche; however, an overall increase in their number does not necessarily promote hematopoiesis. Because the activity of osteoblasts and osteoclasts is coordinately regulated, we hypothesized that active bone-resorbing osteoclasts would participate in HSC niche maintenance. Mice treated with bisphosphonates exhibited a decrease in proportion and absolute number of Lin(-)cKit(+)Sca1(+) Flk2(-) (LKS Flk2(-)) and long-term culture-initiating cells in bone marrow (BM).

In vivo generation of beta-cell-like cells from CD34(+) cells differentiated from human embryonic stem cells.

Objective: CD34(+) cells, present within the bone marrow, have previously been shown to possess pancreatic endocrine potential. Based on this observation, we explored the capacity of CD34(+) cells derived in culture from the differentiation of human embryonic stem cells (hESC), for their in vivo pancreatic endocrine capacity.

Materials And Methods: Sheep were transplanted with hESC-derived CD34(+) cells, as well as nonsorted differentiated cultures.

Persistent circulating human insulin in sheep transplanted in utero with human mesenchymal stem cells.

Objective: To determine if mesenchymal stem cells (MSC) derived from human fetal pancreatic tissue (pMSC) would engraft and differentiate in sheep pancreas following transplantation in utero.

Materials And Methods: A three-step culture system was established for generating human fetal pMSC. Sheep fetuses were transplanted during the fetal transplant receptivity period with human pMSC and evaluated for in situ and functional engraftment in their pancreas, liver, and bone marrow.

The effect of hypoxia and stem cell source on haemoglobin switching.

This study investigated whether relative changes that accompany the naturally occurring shifts in haematopoietic sites during human development play a role in haemoglobin (Hb) switching or whether Hb switching is innately programmed into cells. CD34(+)/Lineage(-) haematopoietic stem/progenitor cells (HSCs) were isolated from human fetal liver (F-LVR), cord blood (CB), and adult bone marrow (ABM), and the Hb was characterized by flow cytometry on cultures that generated enucleated red cells. All feeder layers (stroma from F-LVR, ABM, and human fetal aorta) enhanced cell proliferation and erythropoiesis but did not affect Hb type.