The role of ALK4 signaling in skeletal homeostasis and pathogenesis

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New biologically-based therapeutics that target signaling pathways have tremendous potential to provide novel treatments for chronic and often debilitating diseases. One such approach is the creation of ligand traps, which capture proteins that exhibit high-affinity binding to a receptor extracellular domain, and subsequently prevent these molecules from activating target cells. Preclinical studies employing ligand traps for Acvr2A/B (2A/B-LT), type 2 receptors in the TGF-β superfamily, collectively demonstrate that reducing canonical Smad2/3 signaling reduces the disease burden in mouse models of chronic illnesses. Based on these findings, ongoing and planned clinical trials are evaluating the efficacy of 2A/B-LT in patients with obesity, chronic obstructive pulmonary disease, cancer-induced cachexia, type 2 diabetes, rheumatoid arthritis, and anemia of inflammation. Most of these chronic illnesses also have skeletal manifestations, and beneficial changes in bone mass and strength have been reported in mice treated with 2A/B-LT. However, why 2A/B-LT treatment has positive effects on the skeleton, what cell populations are directly affected by 2A/B-LT, and the mechanism(s) by which decreasing Smad2/3 activation regulates bone cell responses are largely unknown. Filling these gaps in knowledge will be critical to identifying any skeletal side effects of using 2A/B-LT. Findings from our lab suggest that genetic deletion of Alk4, a type 1 receptor within the TGF-β superfamily, in early osteoprogenitors results in increased bone mass in mice. Furthermore, data from our group and others suggests bone homeostasis may be influenced by opposing changes in Smad2/3 and Smad1/5/8 signaling due to shared usage of Acvr2A/B between BMPs and Alk4-activating ligands. We therefore hypothesize that circulating ligands signaling through Alk4 regulate bone homeostasis and pathogenesis by competition between Smad2/3 and Smad1/5/8 signaling. Completion of the aims in our proposal will allow us to identify the bone cell targets of these TGF-β superfamily ligand traps (SA1), determine whether the ligand trap Alk4-FC has therapeutic potential in bone (SA2), examine the efficacy of Alk4-FC in 2 chronic disease models (SA3), and inform about the molecular events that comprise the skeletal response to ligands that activate Smad2/3 signaling (SA4). The questions addressed in this proposal are significant because they fill a critical knowledge gap about potential off- target effects on the skeleton that may occur when 2A/B-LT is used to treat chronic diseases. We believe the results we obtain by completing our studies are impactful because they highlight the potential of using 2A/B-LT and/or Alk4-FC to prevent/modulate the generalized bone loss that occurs with age, as well as to enhance bone fracture repair. Further, our studies will significantly advance our understanding of the role of Smad2/3 and Smad1/5/8 signaling in the adult skeleton, and provide a framework for understanding TGF-β superfamily biology as a mechanism for ensuring homeostasis in bone and other target tissues.