The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis.
The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis.
复制标题
DOI：
10.1002/jcp.25976
复制
发表时间：
2018-03
影响因子：
5.6
通讯作者：
Reagan MR
中科院分区：
文献类型：
--
作者：
Fairfield H;Falank C;Harris E;Demambro V;McDonald M;Pettitt JA;Mohanty ST;Croucher P;Kramer I;Kneissel M;Rosen CJ;Reagan MR
骨髓龛是一个动态的、复杂的微环境，既可以调节，也可以受骨基质的调节。在骨髓(BM)中，间充质基质细胞(MSC)前体细胞处于多能状态，并保持向成骨、成脂或成软骨方向分化的能力，以响应众多生化信号。这些信号可以在不同的病理状态下改变，包括但不限于骨质疏松性骨折、系统性肥胖症和骨归巢癌症的存在。在这里，我们提供了来自骨基质(骨细胞)的信号通过调节骨髓中的脂肪生成来决定骨髓脂肪的证据。具体地说，我们发现生理相关水平的硬化素(Score)可以诱导3T3-L1细胞、小鼠耳源性和骨髓来源的MSCs以及人BM来源的MSCs分化为脂肪。我们证明SOST诱导脂肪形成的机制是通过抑制前脂肪细胞中的Wnt信号。我们还证明，体内硬化素的减少，通过遗传和药物方法，显著减少骨髓脂肪组织(BMAT)的形成。总体而言，这项工作证明了SOST在调控BM-脂肪细胞前体细胞命运决定中的直接作用。这提供了一种新的机制，即BMAT受局部骨微环境的控制，这可能与某些涉及骨髓脂肪的疾病的发病机制有关。重要的是，随着抗硬化素治疗处于骨质疏松症治疗的前沿，以及对BMAT在疾病中的作用的进一步认识，这些数据可能具有重要的临床意义。
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.
登录
查看更多内容
影响因子：
6.2
作者：
Genant, Harry K.;Engelke, Klaus;Libanati, Cesar
通讯作者：
Libanati, Cesar
影响因子：
6.2
作者：
Li, Xiaodong;Ominsky, Michael S.;Paszty, Chris
通讯作者：
Paszty, Chris
影响因子：
7.7
作者：
Gustafson B;Smith U
通讯作者：
Smith U
影响因子：
5.6
作者：
Doucette CR;Horowitz MC;Berry R;MacDougald OA;Anunciado-Koza R;Koza RA;Rosen CJ
通讯作者：
Rosen CJ
影响因子：
16.6
作者：
Florio M;Gunasekaran K;Stolina M;Li X;Liu L;Tipton B;Salimi-Moosavi H;Asuncion FJ;Li C;Sun B;Tan HL;Zhang L;Han CY;Case R;Duguay AN;Grisanti M;Stevens J;Pretorius JK;Pacheco E;Jones H;Chen Q;Soriano BD;Wen J;Heron B;Jacobsen FW;Brisan E;Richards WG;Ke HZ;Ominsky MS
通讯作者：
Ominsky MS