The skeletal cell‐derived molecule sclerostin drives bone marrow adipogenesis

Abstract

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.

Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes

“…Overall, there are a multitude of ways in which MAT and BMAs may contribute to tumor growth, and clinically targeting MAT is an interesting and innovative concept. It is possible that therapies that build bone may also inhibit MAT, as we have recently demonstrated with anti-sclerostin antibodies [54,57], and as others have found with PTH [47] and leptin [69]. The FGF family members may also hold promise for targeting to modulate not only bone, but also MAT.…”

“…Other researchers have shown that osteoclasts play a key role in determining if a myeloma cell will remain dormant or proliferate [49]. Osteocytes also dictate myeloma cell fate and bone remodeling [50–52], and we have shown that targeting osteocyte-derived sclerostin is an effective way to combat myeloma-induced bone disease in mouse models as well as decrease MAT [53,54]. …”

“…Many researchers have speculated that MAT impedes bone development due to direct effects on mature osteoblasts or MSCs, but direct evidence is lacking due to the challenges of specifically modulating MAT. Interestingly, many of the signaling pathways in MSCs that induce osteogenic differentiation inhibit adipogenic differentiation, such as Wnt [54,57] and parathyroid hormone (PTH) signaling [47,58]. Thus, increased adipogenesis may decrease the pool of progenitor cells able to undergo osteogenesis, which would decrease the number of osteoblasts in the niche and likely decrease bone volume fractions in cortical and trabecular bone regions.…”

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…Kennell and MacDougald investigated Xenopus Wnt8 and FZD1 or FZD2 chimeras and established a role for both β-catenin-dependent and β-catenin-independent mechanisms in mesenchymal cell fate and adipogenesis (57). Conversely, in a recent report, inhibition of Wnt signalling through the Wnt-inhibitory molecule sclerostin led to spontaneous adipogenesis of pre-adipocytes and mesenchymal precursors (58), supporting the concept of Wnt signalling controlling the adipogenic switch.…”

Mechanical signals protect stem cell lineage selection, preserving the bone and muscle phenotypes in obesity

“…61 Concurrent with increases in total body and visceral adiposity, high-fat diet models of obesity in rodents show increased marrow fat, 47,62 increased commitment to adipogenesis, and alterations in MSC differentiation potential. 63 MSC differentiation is also regulated by the Wnt signaling pathway, 64–66 and it is understood that osteoblastogenesis and adipogenesis in the marrow generally maintain an inverse relationship. Adipocyte commitment is often associated with reduced bone formation, as seen in models of microgravity, 67,68 ovarian hormone depletion, 69,70 and aging.…”