Potential Role for the Ubiquitin Ligase SIAH2 in Modulating Bone Morphology and Adiposity

Marrow adipose expansion, with obesity or ageing, increases fracture risk. Skeletal stem cells can commit to osteoblast or adipocyte endpoints, an inverse relationship influenced by peroxisome proliferator-activated receptor gamma (PPARγ). Seven in absentia homologue 2 (SIAH2) is a ubiquitin ligase that acts in peripheral adipose tissue stromal progenitors, promoting PPARγ activity and adipogenesis. The pivotal role of PPARγ in bone marrow adipose tissue accumulation prompted us to evaluate SIAH2's role in the balance between osteogenesis and adipogenesis. Using adherent skeletal stem and/or progenitor cells (SSPCs) isolated from the marrow of wild-type (WT) and Siah2^-/- mice, we assessed in vitro osteogenic and adipogenic capacity. Bone morphology and adiposity were assessed, in vivo, using WT and Siah2^-/- mice in the context of dietary, high-fat diet, and pharmacological, rosiglitazone, PPARγ stimulation. We hypothesized increased osteogenesis in Siah2^-/- SSPCs and expected Siah2^-/- mice would be resistant to the effects of PPARγ activation on trabecular morphology and marrow fat expansion. Our results show that Siah2^-/- SSPCs display increased capacity for both osteogenesis and adipogenesis in vitro. Further, exploratory experiments in vivo indicate Siah2^-/- mice have fewer, yet thicker, trabeculae on a low fat diet, while Siah2^-/- mice on a high-fat diet paired with rosiglitazone trend toward more marrow adipose, decreased bone mass and increased trabecular spacing compared to WT. Our results suggest SIAH2 moderates both osteogenic and adipogenic commitment as the absence of SIAH2 results in progenitor cells that will more readily commit to either outcome. These observations underscore SIAH2's context-specific modulatory effects on PPARγ activities determined by tissue, nutrients and pharmacological cues.