Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta

Abstract

Osteogenesis Imperfecta (OI) is a heritable disorder of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations1. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms2. Here, we show that excessive transforming growth factor-beta (TGFβ) signaling is a mechanism of OI in both recessive (Crtap−/−) and dominant (Col1a2tm1.1Mcbr) OI mouse models. In the skeleton, we find higher expression of TGFβ target genes, ratio of pSmad2/Smad2 protein, and in vivo Smad2 reporter activity. Anti-TGFβ treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI, and improves the lung abnormalities in Crtap−/− mice. Moreover, type I collagen of Crtap−/− mice shows reduced binding to the small leucine rich proteoglycan decorin, a known regulator of TGFβ activity3–4. Hence, altered TGFβ matrix-cell signaling is a primary mechanism in the pathogenesis of OI, and could be a promising target for the treatment of OI.

Osteogenesis imperfecta

“…TGFβ neutralizing antibodies can improve trabecu lar bone mass, cortical thickness and bone strength in Crtap −/− mice through combined reductions in both osteoclast and osteoblast activity. In addition, inhibition of the TGFβ pathway improves lung ultrastructure in this model 226 . Similar trabecular results were observed in Col1a2 +/p.G610C (Amish) mice, suggesting that exces sive TGFβ signalling might have a role in dominant and recessive models of osteogenesis imperfecta 226 .…”

“…In addition, inhibition of the TGFβ pathway improves lung ultrastructure in this model 226 . Similar trabecular results were observed in Col1a2 +/p.G610C (Amish) mice, suggesting that exces sive TGFβ signalling might have a role in dominant and recessive models of osteogenesis imperfecta 226 .…”

“…Increased TGFβ signalling has been observed in osteoblasts of patients 225 and in mouse models of osteogenesis imperfecta 31,226 ; it is not yet clear to what extent the detected increase is a bystander effect. TGFβ neutralizing antibodies can improve trabecu lar bone mass, cortical thickness and bone strength in Crtap −/− mice through combined reductions in both osteoclast and osteoblast activity.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Increased TGF-b signaling was shown in mouse models for each form of OI, and the OI phenotype could be rescued by TGFb inhibition, consistent with aberrant TGF-b activity causing the underlying OI bone pathology (Grafe et al 2014). These results emphasize the sensitivity of the TGF-b-mediated balance between bone resorption and deposition; however, further investigations are needed to fully understand the roles of BMP and TGF-b in bone homeostasis and quality.…”

Bone Material Properties in Osteogenesis Imperfecta

“…(101) In terms of future therapeutic interventions, new approaches to improving the intrinsic material properties of bone would appear attractive but may not be practicable given the underlying issue of matrix disorganization. Increasing the proportion of normal collagen within the matrix would require implementation of cellular or genetic approaches.…”