Parmodulins as an Anti-Resorptive and Anti-Inflammatory Therapy for Metabolic Bone Disease

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Summary: Current therapies for metabolic bone diseases are effective. However, their use is associated with rare but significant side effects, which limit their acceptance by patients. The most widely used drugs, bisphosphonates and denosumab, inhibit both resorption and formation and this dual action may lead to the development of severe complications (osteonecrosis of the jaw and sub-trochanteric fractures). Therefore, there is a pressing need for new therapies for these conditions that are effective, have a decreased risk of complications and will be more accepted by patients. The identification of agents that inhibit resorption and either have no effect or stimulate formation is likely critical for finding therapies with fewer side effects. Inflammation is known to be a significant component of metabolic bone diseases like rheumatoid arthritis, inflammatory bowel disease and psoriasis and also osteoporosis and Paget's disease. We have found that osteoclast precursor cells transiently express protease activated receptor 1 (PAR1) during their differentiation into mature osteoclasts. This is significant because PAR1 modulates a variety of responses in cells, including inflammation and apoptosis. Both in vitro and in vivo we found that PAR1 inhibited inflammatory osteoclastogenic responses, particularly those stimulated by tumor necrosis factor α (TNFα) since in PAR1 deficient cells or mice responses to TNFα were markedly enhanced. Many inhibitory effects of PAR1 on inflammation and apoptosis are mediated by the enzyme, activated protein C (APC). Recently, a group of small molecules, the parmodulins, were identified as selective agonist/antagonists of PAR1. These agents mimic APC's antiinflammatory and antiapoptotic actions, without affecting its anticoagulative action. In preliminary data we show that the parmodulin, ML-161, specifically inhibited in vitro osteoclastogenesis without affecting osteoblast collagen synthesis or alkaline phosphatase activity. In this application we will test the hypothesis that parmodulins are a potential new therapy for metabolic bone diseases, which may have fewer serious side effects. In specific aim 1 we will provide a detailed analysis of the effects of ML-161 and NRD-21 on in vitro osteoclast and osteoblast formation and function. In specific aim 2 we will examine the in vivo ability of ML-161 and NRD-21 to inhibit the inflammatory response of bone to TNFα. If successful, these studies will provide the foundation for more detailed studies of the effects of parmodulins on murine models of bone disease due to sex steroid withdrawal, aging and inflammatory conditions.