Transforming Growth Factor β2 Inhibits Adipocyte Differentiation Induced by Skeletal Unloading in Rat Bone Marrow Stroma

Abstract

Skeletal unloading induced by hindlimb suspension in rats reduces bone formation and induces osteopenia, but its effect on adipogenesis is unknown. We assessed the effects of unloading and transforming growth factor (TGF) ␤2 on bone marrow stromal cell adipocyte differentiation in relation with osteoblast differentiation. Skeletal unloading rapidly (4 -7 days) decreased osteoblast transcription factor Runx2, osteocalcin (OC), and type I collagen messenger RNA (mRNA) levels and reduced bone formation in the long bone metaphysis. Conversely, unloading increased expression of the adipocyte transcription factor peroxisome proliferatoractivated receptor ␥2 (PPAR␥2) at 4 days and increased expression of the adipocyte differentiation genes lipoprotein lipase (LPL) and aP2 in the bone marrow stroma at 7 days. Consistently, unloading increased the number and volume of adipocytes in the bone marrow stroma. Continuous (0 -7 days) and late (4 -7 days) treatments with TGF-␤2 corrected the abnormal expression of Cbfa1/Runx2, OC, and type I collagen mRNAs and normalized bone formation in unloaded metaphyseal bone. Moreover, both TGF-␤2 treatments decreased PPAR␥2 and C/EBP␣ mRNA levels at 4 days and normalized aP2 and LPL expression and adipocyte number and volume at 7 days. These results show that skeletal unloading increases adipocyte differentiation concomitantly with inhibition of osteoblast differentiation. These abnormalities are prevented and reversed by TGF-␤2, suggesting a role for TGF-␤ in the control of adipogenic differentiation in the bone marrow stroma. (J Bone Miner Res 2002;17:668 -677)

Thy-1 Expression in Human Fibroblast Subsets Defines Myofibroblastic or Lipofibroblastic Phenotypes

“…Indeed, mediators implicated in maintaining myofibroblast formation such as TGF␤ and TNF␣, have the capacity to impair adipogenesis. 18,57,58 Extracellular matrix components also play important functional roles in their microenvironment. For example, fibronectin and thrombospondin-1 are both essential for TGF␤-induced myofibroblast formation 39,59 and their presence may affect the outcome of differentiation.…”

Identification of quantitative trait loci associated with bone traits and body weight in an F2 resource population of chickens

“…6.3 *Significant QTL are defined by an F-ratio greater than the 5% genome-wise threshold. 1 Trait abbreviations are defined in Table I. 2 Position of QTL relative to the first marker genotyped on the chromosome, see Table II.…”

“…Another candidate gene, transforming growth factor-β2 (TGFβ2), is located on chromosome 3 near the peak affecting BMD of the tibia at 35 wk of age, as well as bone breaking force of the tibia. TGFβ2 influences bone and adipose cell differentiation [1,6,8,53], and a polymorphism in the promoter of this gene has been associated with BMD and BMC of the tibia at 8 wk in a chicken population derived from a cross between broiler sires and Leghorn dams [31].…”

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

“…Another bone growth factor that is a member of BMP family is transforming growth factor b (TGFb or TGFB1) that promotes osteoblastic cell proliferation, function, and survival (75). In vivo, TGFb does not prevent bone loss induced by ovariectomy (76) but prevents immobilization-related bone loss caused by decreased osteoblastogenesis (77,78). Inhibins (Inh), activins, and myostatins (GDF8) are other members of the TGFb superfamily that control bone metabolism (79).…”