Role of IL-17 receptor A in aging bone remodeling

Summary: Inflammatory cytokines are potent stimulators of osteoclastic bone resorption. During aging, there are increased levels of these inflammatory mediators that are widely associated with perturbed skeletal homeostasis, and more recently fracture healing. During the past decade, the influence of inflammatory signals on bone health has been the focus of many laboratories. One particular family of pro-inflammatory cytokines (IL-17 family) has been increasingly shown to play key roles in controlling skeletal homeostasis. We came across the discovery that serum levels of IL-17a in fractured old mice were dramatically increased compared to young controls. Conditional deletion of the main receptor for IL-17a (IL-17ra) in osteoclasts resulted in decreased bone resorption and increased bone mass in vivo. Based on additional preliminary findings, our postulated mechanism underlying IL- 17ra control of bone remodeling involves the newly discovered transcriptional repressor of osteoclastic bone resorption, Runx1. Based on the above, we postulate that deletion of IL-17ra in OCLs will increase bone mass during skeletal homeostasis and promote bone repair through stage specific inhibition of osteoclastic bone resorption by Runx1 during fracture callus remodeling. In Aim 1, we propose to examine the function of OCL-produced IL-17ra and mechanisms via which it modulates bone remodeling during homeostasis in the aging skeleton. Specifically, we will determine if loss of IL-17ra in OCLs will increase bone mass in aging mice (1A). We will then demonstrate that deletion of IL-17ra in OCLs inhibits bone resorption through upregulation of Runx1 (1B). Finally, we will determine if deletion of IL-17ra in OCLs is sufficient to halt ovariectomy-induced bone loss (1C). In the second Aim, we propose to evaluate whether inhibition of IL-17ra or activation of Runx1 in OCLs can stage-dependently control bone healing in aging mice by first evaluating the effects of IL-17ra abrogation on callus remodeling and bone repair in aging mice (2A). We will then examine whether stage-dependent overexpression of Runx1 in OCLs is sufficient to accelerate the healing of senile fractures (2B). Finally, we will devise a therapeutic strategy to accelerate fracture healing in aging mice via delivery of a small molecule to temporally activate Runx1 during callus remodeling (2C). The data obtained from the proposed experiments will reveal new anti-inflammatory downstream signaling pathways that can serve as viable substitutes for the currently available anti-resorptive biologics.