Abstract 15378: Osteoclasts Activation Contributes to Remodeling of the Endosteal Stem Cell Niche in Early Stage Diabetes
Background: We showed that diabetes mellitus (DM) can impinge upon the bone marrow (BM) reservoir of regenerative cells through different mechanisms, including altered gene expression, niche dysfunction, microvascular rarefaction and neuropathy. In particular, a novel form of microangiopathy causes depletion of the stem cell (SC) pool at the level of the endosteal niche. Moreover, endosteal osteoclasts (OCLs) play a crucial role in homeostasis and mobilization of BM SCs.
Objective: We investigated the contribution of OCLs in early alterations of BM SC composition and egression in streptozotocin-induced type 1 diabetic (T1D) mice.
Methods/Results: Flow cytometry studies showed a marked increase in the fraction of lineagenegSca-1poscKitpos (LSK) cells in peripheral blood (PB) of mice with early stage DM (5 weeks) compared with age-matched non-diabetic controls (C) (0.7±0.4 vs 0.2±0.1% of total MNCs, p<0.05). Immunohistochemical analysis of femoral bones showed similar abundance of LSK cells in the BM of T1D and C. However, at later stages of DM (20 weeks), we observed a profound BM remodeling with reduction of the hematopoietic component, fat accumulation and bone rarefaction. Likewise, the number of activated OCLs expressing tartrate resistant acid phosphatase (TRAP), a marker of OCLs activation, increased in trabecular bone since the early DM stage (2.9±0.3 vs 1.6±0.7 cells/mm of endosteal length in C, p<0.01). Protein and mRNA expression of Receptor activator of NF-κB Ligand (RANKL), an inducer of OCL differentiation and activation, was reduced in total BM at 5 weeks of DM (mRNA 0.2±0.03 vs 1.1±0.6 ddCT in C; Protein 11.8±3.7 vs 28.7±10.1 pg/ml, p<0.05 for both comparisons).
Conclusions: Concurrent increases in circulating SCs and endosteal OCLs occur at initial phase of DM, before any apparent alteration of hematopoiesis. OCLs activation may lead to detachment of SCs from the endosteal niche and excessive mobilization, thus resulting in BM exhaustion at later stages. OCL-induced remodeling of the endosteal niche, which contains the most primitive SCs in BM, may contribute to the impairment of regenerative capacity in DM.
- © 2012 by American Heart Association, Inc.