Connecting Bone and Fat: the Potential Role for Sclerostin
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Purpose of Review
Sclerostin (SOST), a protein secreted from mature osteocytes in response to mechanical unloading and other stimuli, inhibits the osteogenic Wnt/β-catenin pathway in mesenchymal stem cells (MSCs) impeding their ability to differentiate into mineralizing osteoblasts. This review summarizes the crosstalk between adipose tissue and the bone. It also reviews the origin, regulation, and role of SOST in osteogenesis and brings attention to an emerging role of this protein in the regulation of adipogenesis.
Bone-derived molecules that drive MSC adipogenesis have not previously been identified, but recent findings suggest that SOST signaling may induce adipogenesis. In vivo SOST acts locally to induce changes in the bone and, in vitro, increases adipogenesis in 3T3-L1 preadipocytes.
SOST is able to induce adipogenesis in certain preadipocytes, however, bone-specific studies are needed to determine the effect of local SOST concentrations in healthy and disease models on bone marrow adipose tissue.
KeywordsSclerostin Adipogenesis Bone marrow adipose tissue Fat LRP Wnt
The authors’ work is supported by MMCRI Start-up funds, a pilot project grant from the NIH/NIGMS (P30GM106391) and the NIH/NIDDK (R24DK092759-01).
Compliance with Ethical Standards
Conflict of Interest
Heather Fairfield, Clifford J. Rosen, and Michaela R. Reagan each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 17.• Berry R, Rodeheffer MS, Rosen CJ, Horowitz MC. Adipose tissue residing progenitors adipocyte lineage progenitors and adipose derived stem cells (ADSC). Curr Mol Biol reports. 2015;1:101–9. doi: 10.1007/s40610-015-0018-y. This is a comprehensive overview of the types of adipose tissue, how each of them functions, and what their similarities and differences are. Specifically, the lineage of each type of adipocyte is outlined in great detail, citing lineage tracing experiments and yielding evidence that bone marrow adipocytes are distinct from white adipocytes. Compilation of numerous findings in this review demonstrates that MSCs that give rise to osteoblasts and adipocytes are osterix positive (neonatal) and both leptin receptor and nestin-positive (adult) determining that the majority of these two cell types arise from a common progenitor population. CrossRefGoogle Scholar
- 18.• Sulston RJ, Learman BS, Zhang B, et al. Increased circulating adiponectin in response to thiazolidinediones: investigating the role of bone marrow adipose tissue. Front Endocrinol (Lausanne). 2016;7:128. doi: 10.3389/fendo.2016.00128. This paper utilizes a model published in 2007 with transgenic overexpression of Wnt10b in osteoblasts and osteocytes (Ocn-Wnt10b) which characterized increased bone (BMD, etc.) and decreased marrow space in these mice. The new paper by Sulston et al. shows direct evidence that (1) increased local Wnt signaling leads to lower MAT and (2) that this signaling is able to partially restrict MAT expansion during treatment with TZD confirming that Wnt signaling is a key regulator of MSC fate determination but also that inhibition of this pathway must be required for normal MAT formation and expansion stimulation of PPARγ in these cells is not enough. Google Scholar
- 19.MacDougald OA, Mandrup S. Adipogenesis: forces that tip the scales. Trends Endocrinol Metab. 13:5–11.Google Scholar
- 22.• Yue R, Zhou BO, Shimada IS, et al. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell. 2016;18:782–96. doi: 10.1016/j.stem.2016.02.015. The leptin receptor (Lepr) was conditionally deleted from long bones during this study (Prx1-Cre;Lepr<fl/fl>) yielding animals with normal body mass. Limb bones from these animals had high bone parameters and reduced bone marrow adipose tissue demonstrating the importance of leptin signaling and energetic requirements in the overall maintenance of the bone marrow microenvironment. CrossRefPubMedGoogle Scholar
- 41.Kügel H, Jung C, Schulte O, Heindel W. Age-and sex-specific differences in the 1 H-spectrum of vertebral bone marrow. J Magn Reson Imaging. 2001;268:263–8.Google Scholar
- 53.• Ukita M, Yamaguchi T, Ohata N, Tamura M. Sclerostin enhances adipocyte differentiation in 3T3-L1 cells. J Cell Biochem. 2015; doi: 10.1002/jcb.25432. This paper by Ukita et al. is the first direct examination of the effect of sclerostin on a preadipocyte. The authors demonstrate increased adipogenesis as evidenced by functional (oil red o) and genetic (qPCR) outputs and suggest that the pro-adipogenic effect of SOST is via its traditional role in canonical Wnt signaling inhibition. This is extremely promising work but does not actually answer the question about the effect that SOST might be having in its local microenvironment. 3T3-L1 cells are preprogrammed as preadipocytes, similar to WAT. As demonstrated by the additional papers highlighted here, preadipocytes from WAT are distinct from bone marrow adipocytes, and thus, bone-specific studies are still required to determine whether changing levels of sclerostin can affect the bone marrow adipose depot. Google Scholar
- 62.Delgado-Calle J, Anderson J, Cregor MD, et al. Bidirectional Notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma. Cancer Res. 2016; doi: 10.1158/0008-5472.CAN-15-1703.PubMedPubMedCentralGoogle Scholar