Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682681
Title: Osteoclast activation contributes to the remodeling of the stem cell niche in diabetes through the modulation of TRPV1 channel
Author: Reni, Carlotta
ISNI:       0000 0004 5914 4842
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Abstract:
Diabetic subjects develop microangiopathy in the bone marrow (BM) resulting in depletion of stem cells (SC) and alteration of SC release upon tissue damage. BM-SC mobilization is a complex process that requires activation of different mechanisms and cell types. In particular, endosteal osteoclast activation was shown to be essential for inducing BM-SC mobilization. Since previous studies showed that the endosteal BM niche is the most affected compartment, the role of osteoclast activation in SC depauperization during diabetes was investigated. The increased number of activated osteoclasts in trabecular bones since the early stage of the disease (5 weeks) was demonstrated using a mouse model of diabetes. At the same time-point a marked increase in the fraction of lineage(neg)Sca-i(pos)cKit(pos) cells in the peripheral blood of diabetic mice compared with non-diabetic controls was also observed, thus suggesting increased SC mobilization that anticipates subsequent depletion in BM and peripheral circulation. Intriguingly, the canonical pathway for osteoclast activation (Receptor Activator of NF-KB Ligand/osteoprotegerin pathway) was not involved in diabetes-induced osteoclast activation, implying a non-canonical mechanism. Interestingly, induction of acidosis in the BM was observed during diabetes in vivo and a mild reduction in the pH of culturing media was sufficient to enhance the differentiation of BM-derived cells into osteoclast-like cells in vitro. Moreover, the expression of Transient receptor potential V1 (TRPV1) was increased in the diabetic BM and in BM cells cultured under acidosis. Finally, using gain-and loss-of-function approaches in vitro, it was demonstrated that acidosis triggers osteoclast activation trough the modulation of TRPV1. The increased acidosis in the diabetic BM with consequent increase in TRPV1 expression promotes osteoclast activation in diabetes. Osteoclast activation may lead to SC detachment from the endosteal niche and their excessive mobilization, resulting in the exhaustion of the BM-SC pool at later stages. Osteoclast-induced remodeling of the endosteal niche, which contains the most primitive SCs in the BM, may contribute to the impairment of regenerative capacity observed in diabetic subjects
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.682681  DOI: Not available
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