Bone Abstracts (2015) 4 IS12 | DOI: 10.1530/boneabs.4.IS12

The role of TGF[beta] in high turnover bone diseases

Susan Schiavi

Boston, Massachusetts, USA.

TGFβ is a family of ubiquitous growth factors that play a prominent role in bone biology. In normal bone remodeling, TGFβ1 released from the bone matrix by osteoclasts, attracts mesenchymal stem cells to sites of resorption thereby ensuring that new bone restores eroded older bone. TGFβ also promotes osteoblast proliferation but later restricts osteoblast maturation by repressing the expression of genes involved in bone formation. Recent evidence has demonstrated that inhibition of SMAD3 dependent TGFβ signaling is required for the decreased sclerostin expression that occurs in response to mechanical loading. Similar to other autocrine/paracrine factors, TGFβ’s diverse activities on bone are dependent on regulation by negative and positive regulators that orchestrate specific TGFβ functions in a spatial and temporal manner. Emerging evidence suggests that dysregulation of this pathway and/or its regulators contribute to a variety of bone pathologies including renal Camurati–Engelmann disease, renal osteodystrophy, osteogenesis imperfecta, high turnover osteoporosis, and osteoarthritis. For example, TGFβ is elevated in serum, bone and other tissues of individuals with chronic kidney disease. In preclinical studies TGFβ neutralization normalized bone turnover markers, decreased bone formation, improved trabecular and cortical architecture and reduced cortical porosity in the setting of high turnover renal osteodystrophy. TGFβ neutralization decreased SOST mRNA expression and restored repressed β-catenin to normal levels as evidenced by enhanced expression of genes downstream of Wnt/β-catenin signaling. Since TGFβ is known for temporal actions on osteoblasts that first promote and then attenuate osteoblast differentiation, it is conceivable that continuous pathologic over-expression could be associated with sustained inhibition of osteoblast maturation as exemplified by changes in Wnt/β-catenin signaling. Further exploration of TGFβ’s mechanism of action on renal and other bone diseases has been initiated using a network based informatic approach.

Disclosure: The author declared no competing interests.

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