Fibrillin-1 (FBN1) is a structural component of microfibrils in the extracellular matrix that plays a role in tissue development. Genetic defects in FBN1 are associated with a number of clinical conditions including systemic sclerosis (SSc)/scleroderma. In this issue, Chen et al. report that the osteopenia in a mutant “tight skin” mouse model of SSc (in which Fbn1 deficiency is due to a partial duplication of the Fbn1 gene) is caused, at least in part, by an increase in IL-4 signaling in bone marrow mesenchymal stem cells (BMMSCs). This activation of IL-4 signaling in BMMSCs favors adipogenic differentiation and prevents osteoblast differentiation in an mTORC1-dependent manner.

Undoubtedly, this paper covers a lot of ground, from the bone pathology in this model of SSc, to the molecular pathogenesis and treatment with the mTOR inhibitor rapamycin. There is no doubt that the therapeutic aspect is the most original, exciting, and important one of this exhaustive study, mainly because it is the least expected.

First of all, this paper provides a long awaited explanation for the ability of IL-4 overexpression in cells of the osteoblast lineage to cause bone loss by decreasing bone formation, an observation that was first reported by the Perlmutter group 20 years ago. This is a very stimulating paper in a rapidly evolving field for several reasons. The model of Fbn1 mutation used in this paper is not a loss of function mutation. Hence, it will be important to determine if the increase in osteogenesis seen in Fbn1 loss of function mouse models will be explained by the same or by a different mechanism. Given the opposite nature of the bone phenotype in the two mouse models this is the most urgent question to address.

In a broader sense, the fact that activating the mTORC1 pathway would down-regulate osteogenesis is interesting because it seems counterintuitive. Indeed, osteogenesis is a process that requires a continuous and high level of protein synthesis; therefore, one would anticipate that activating the mTORC1 pathway would have a beneficial effect on osteogenesis, not a deleterious one. This is what has been observed in other, albeit different, mouse models, and it will be interesting to investigate the molecular basis of the differences between the tight skin mice and other models.

This study presents a large amount of data on the role of the FBN1/TGF-β/IL4Rα/mTOR cascade in BBMSC lineage selection. As acknowledged by the authors, it is clear that there is more to this story and that it is only the beginning of a long investigation. Further work to address the two key issues highlighted above will help to elucidate the regulation of bone formation by the extracellular matrix and the mechanisms whereby IL-4 signaling in cells of the osteoblast lineage can affect bone.

, et al
J. Exp. Med.