Effect of Reduced c‐Kit Signaling on Bone Marrow Adiposity

Abstract

c-Kit (CD117) is required for normal differentiation of osteoblasts from bone marrow stromal cells and for normal bone formation. Osteoblasts and adipocytes originate from a common progenitor cell, and a reciprocal relationship in differentiation of the two lineages is often observed. Therefore, the effects of abnormal c-kit signaling on bone marrow adiposity and adipocyte precursor pool size were evaluated in mouse strains with loss of function mutations in kit receptor or kit ligand. Additionally, to determine whether short-duration pharmacological disruption of kit signaling influences bone marrow adiposity, we administered the kit receptor antagonist gleevec (imatinib mesilate) for 1 week to middle aged (13-month-old) male rats known to have high levels of bone marrow fat. Compared to wild-type littermates, adipocytes were absent and adipocyte precursors greatly reduced in bone marrow from kit receptor-deficient Kit W/W-m mice. Administration of secreted kit ligand to membrane-associated kit ligand-deficient Kit Sl/Sl-d mice was ineffective in inducing bone marrow adipogenesis. These findings suggest that activation of kit receptor by the membrane-associated form of kit ligand is required for kit signaling to promote bone marrow adipogenesis in mice. Rats treated with gleevec had lower adipocyte density compared to age-matched controls, suggesting that kit signaling is required to maintain normal bone marrow adiposity. Taken together, our results indicate that c-Kit signaling plays an important but previously unsuspected role in regulating bone marrow adiposity. Anat Rec, 294:1126Rec, 294: -1134Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.Key words: hematopoietic stem cell; mesenchymal stem cell; adipocyte; mast cell; receptor tyrosine kinase; gleevec (imatinib mesilate)Osteoblasts and adipocytes are derived from a common bone marrow progenitor (Prockop, 1997;Vaananen, 2005;Valtieri and Sorrentino, 2008). The primary function of osteoblasts is well defined. Osteoblasts generate bone matrix to support bone growth, turnover, and remodeling. Additionally, osteoblasts have been reported to participate in hematopoietic stem cell mobilization from their bone marrow niche and to support hematopoiesis (Nagayoshi et al., 2006;Mayack and Wagers, 2008). In contrast, the physiological significance of adipocytes residing within bone marrow is less well defined.Most fat depots act as dynamic energy reservoirs to maintain circulating triglyceride and free fatty acid levels (Caserta et al., 2001). During severe caloric restriction, fat catabolism becomes an important source of energy and peripheral fat depots decline in mass. In contrast, severe caloric restriction is associated with increased bone marrow adiposity (Batista et al., 1988;Bohm, 2000;Cui et al., 2006;Duque, 2008;Bredella et al., 2009). Bone marrow adipocytes sequester and esterify fatty acids during starvation, a finding which has fostered the belief that the bone marrow fat depot does not function as an important energy reservoir for peripheral tissu...

Failure to generate bone marrow adipocytes does not protect mice from ovariectomy-induced osteopenia

“…Secreted kit ligand binds to and activates kit receptor but is unable to duplicate all of the actions of the membrane-associated ligand [51, 54, 55]. As a consequence, kit Sl/Sl-d mice are sterile, anemic, osteopenic, have elevated osteoclast perimeter and have no marrow adipocytes [24]. Thus, activation of kit signaling through kit receptor by membrane-associated kit ligand appears necessary for differentiation of a variety of marrow-derived cells, including adipocytes.…”

“…However, in spite of a strong inverse association between bone marrow fat and bone mass, it has proven difficult to directly test the hypothesis that excess fat accumulation in bone marrow is responsible for ovx-induced osteopenia. In this regard, we recently reported that kit receptor-deficient kit W/W-v mice have no bone marrow adipocytes [24] but are able to produce osteoblasts and osteoclasts. We therefore reasoned that if bone marrow adipose tissue contributes to the detrimental skeletal effects of estrogen deficiency, kit W/W-v mice would be resistant to ovx-induced osteopenia.…”

Bone Marrow Adipocytes: The Enigmatic Components of the Hematopoietic Stem Cell Niche

“…The underlying mechanisms are not completely understood but c-kit signaling has been suggested to couple MSC and HSC differentiation in BM. In this regard, loss of function mutations in the c-kit receptor and membrane-bound kit-ligand result in certain hematopoietic defects such as anemia and mast cell depletion, and absence of BMA in long bones and lumbar vertebrae [61].…”

Metabolic Coupling Between Bone Marrow Adipose Tissue and Hematopoiesis

“…Loss of function mutations in c-kit receptor and kit-ligand can result in anemia, mast cell deficiency, altered body composition, and skeletal abnormalities. Mutations leading to global reduction in c-kit receptor function (e.g., kit W/Wv ) and m-kit ligand function (e.g., kit Sl/Sld ) in mice also result in absence of MAT in long bones and lumbar vertebrae [65]. A deficiency in kit signaling in mice prevents ovariectomy-induced increase in MAT and accentuates bone loss in hindlimb-unloaded mice [66, 38].…”

“…Kit Sh/Sh mice have a mutation in a regulatory element leading to cell-specific loss of kit signaling. The mice are mast cell-deficient but in contrast to kit W/Wv and kit Sl/Sld are not anemic and have MAT, indicating that the absence of MAT is due to kit signaling insufficiency and not mast cell deficiency, per se [65]. Adoptive transfer of WT bone marrow into kit W/Wv mice was effective in replacing kit W/Wv HSCs with WT HSCs but, surprisingly, did not result in MAT infiltration [38].…”