The skeletal cell‐derived molecule sclerostin drives bone marrow adipogenesis

The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi‐potent state and retain the capacity to differentiate down osteoblastic, adipogenic, o...

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Published in:Journal of cellular physiology 2018-02, Vol.233 (2), p.1156-1167
Main Authors: Fairfield, Heather, Falank, Carolyne, Harris, Elizabeth, Demambro, Victoria, McDonald, Michelle, Pettitt, Jessica A., Mohanty, Sindhu T., Croucher, Peter, Kramer, Ina, Kneissel, Michaela, Rosen, Clifford J., Reagan, Michaela R.
Format: Article
Language:English
Subjects:
3T3-L1 Cells
Adipocytes
Adipocytes - metabolism
Adipogenesis
Adipose tissue
Adipose Tissue - cytology
Adipose Tissue - metabolism
Adiposity
Animals
Biocompatibility
Biomedical materials
Bone marrow
bone marrow adipose
Bone Marrow Cells - metabolism
bone marrow microenvironment
Bone matrix
Cues
Culture Media, Conditioned - metabolism
Glycoproteins - deficiency
Glycoproteins - genetics
Glycoproteins - metabolism
Homing
In vivo methods and tests
Male
Mesenchymal Stem Cells - metabolism
Mesenchyme
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteoblasts
Osteocytes
Osteocytes - metabolism
osteocyte‐derived factors
Osteoporosis
Paracrine Communication
Pathogenesis
Phenotype
sclerostin
Signaling
SOST protein
Stem Cell Niche
Wnt protein
Wnt Signaling Pathway
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Summary:The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi‐potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic‐induced fracture, systemic adiposity, and the presence of bone‐homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt‐inhibitory molecule secreted from bone matrix‐embedded osteocytes, can induce adipogenesis in 3T3‐L1 cells, mouse ear‐ and BM‐derived MSCs, and human BM‐derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre‐adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM‐adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti‐sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications. Sclerostin, a gene that encodes the SOST protein, is expressed by osteocytes within cortical and trabecular bone. We found that SOST protein can regulate bone marrow progenitor cell differentiation by not only inhibiting osteogenesis, but also inducing bone marrow adipogenesis. This novel role for sclerostin in development of bone marrow adipose suggests that sclerostin‐targeting therapies may not only increase osteogenesis, but also decrease bone marrow adipogenesis, which could have wide clinical implications.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.25976