Abstract
Healthy bone remodeling results from a balanced bone formation and bone resorption realized by bone-forming osteoblasts and bone-resorbing osteoclasts, respectively. Recently, Thy-1 (CD90) was identified as positive regulator of osteoblast differentiation and activation, thus, promoting bone formation while concurrently inhibiting adipogenesis and obesity in mice. Additionally, Thy-1 did not affect bone resorption. An obesity-related co-morbidity that is increasing in prevalence is a disturbed bone formation resulting in an increased fracture risk. The underlying mechanisms of obesity-induced bone alterations are not yet fully elucidated and therefore therapy options for efficient bone-anabolic treatments are limited. Therefore, we investigated the impact of Thy-1 on bone metabolism under obese conditions. Indeed, high fat diet (HFD) induced obese mice lacking Thy-1 (Thy-1−/−) showed increased body fat mass compared to wildtype (WT) mice while bone mass (−38%) and formation (−57%) were decreased as shown by micro-computed tomography (μCT) measurement, histological analysis, and fourier-transform infrared spectroscopy (FTIR). Interestingly, under obese conditions, lack of Thy-1 affected both osteoblast and osteoclast function. Number (−30%) and activity of osteoblasts were decreased in obese Thy-1−/− mice while osteoclast number (+39%) and activity were increased. Facilitated bone marrow fat accumulation (+56%) in obese Thy-1−/− mice compared to obese WT mice was associated with upregulated tumor necrosis factor α (Tnfα, +46%) and colony stimulating factor 1 receptor (Csf1r) expression, strong promoters of osteoclast differentiation. Moreover, lack of Thy-1 was accompanied by a reduction of osteoprotegerin (Tnfrsf11b) expression (−36%), an inhibitor of osteoclast differentiation. Altered Tnfα, Csf1r, and Tnfrsf11b expression might be responsible for elevated osteoclast activity in obese Thy-1-deficient mice. In summary, our findings show that lack of Thy-1 promotes obesity under HFD conditions while concurrently decreasing bone mass and formation. Mechanistic studies revealed that under obese conditions lack of Thy-1 impairs both bone formation and bone resorption.
Highlights
Healthy bone remodeling is a result of balanced bone formation realized bone-forming osteoblasts and bone-resorption mediated by bone resorbing osteoclasts (Crockett et al, 2011)
Since diet-induced obesity alters bone remodeling leading to decreased femoral trabecular bone mass in mice (Cao et al, 2009, 2010; Halade et al, 2011; Patsch et al, 2011; Picke et al, 2018b), we investigated the impact of Thy-1 on the disturbed bone remodeling in obesity
Bone remodeling is a result of the balanced activity of boneforming osteoblasts and bone-resorbing osteoclasts resulting in a similar bone formation and resorption rate (Crockett et al, 2011)
Summary
Healthy bone remodeling is a result of balanced bone formation realized bone-forming osteoblasts and bone-resorption mediated by bone resorbing osteoclasts (Crockett et al, 2011). It was discovered that Thy-1 controls fate decision of MSCs regarding differentiation into mature bone-forming osteoblasts or fatstoring adipocytes in vitro and in vivo (Hosoya et al, 2012; Chung et al, 2013; Woeller et al, 2015; Paine et al, 2018; Picke et al, 2018a). Mice lacking Thy-1 display a reduced osteogenic and increased adipogenic differentiation capacity, resulting in decreased bone mass and quality and concurrently, elevated body and bone marrow fat mass (Woeller et al, 2015; Paine et al, 2018; Picke et al, 2018a). The translational potential of these findings was underlined by the detection of strongly reduced levels of soluble Thy-1 in serum of patients with diminished bone formation such as in osteoporotic and obese patients (Picke et al, 2018a)
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