Is Mitf the Missing Puzzle Linking NFATc1 to Osteoclastogenesis

Osteoclasts are bone-resorbing cells essential for maintaining bone mass through modeling and remodeling, In pathological osteolytic conditions, osteoclasts are activated by environmental factors, which disrupt the balance between bone formation and bone resorption, and tip the equilibrium to bone loss. Despite recent advances in restorative dentistry, treating and controlling chronic bone loss in oral cavity is still one of the most challenging tasks for dentists. The condition affects millions of people around the world and is often associated with permanent tooth loss. Although pharmacological agents such as bisphosphonate have much success in preventing metabolic bone loss associated with menopause, it is not effective in preventing bone loss in periodontitis [8]. In periodontitis, chemotactic factors released from oral bacterial infection recruit Band T cells from peripheral blood circulation, and these immune cells are the important local sources of RANKL, which promotes osteoclastogenesis, leading to chronic alveolar bone loss. To develop effective treatment against unregulated osteoclast activation, we need to know how differentiation signals are transmitted from osteoclast surface receptors to the downstream targets and how individual molecules are linked together as a network. Studies of naturally mutated and transgenic osteopetrotic mice have revealed many important genes involving in osteoclastogenesis. Among these, Mitt is unique in its tissue-specific effects restricted to melanocytes, mast cells and osteoclasts. Although osteoclast-specific Mitt has never been identified, melanocyte-specific Mitt and mast cell-specific Mitt are present, believing to be responsible for lineage-specific gene activation. Among all the essential transcription factors in osteoclastogenesis, NFATc1 is considered the master transcription factor, which activation turns on osteoclastogenesis even in the absence of RANKL. Nonetheless, it is not clear how a ubiquitous factor like NFATc1 is able to direct an osteoclast-specific differentiation program. We propose that Mitt, through its tissue-specific effects, is the prime candidate to provide osteoclast-specific transcriptional regulation for NFATc1. In this proposal, we will examine whether the two major Mitt isoforms present in osteoclasts are able to provide osteoclast-specific transcriptional regulation to assist NFATc1 in orchestrating osteoclastogenesis. We will determine if there are differences between the two isoforms in their abilities to promote osteoclastogenesis and transactivate downstream targets. We will also determine their relationships with NFATc1. Experiments are proposed to examine whether and how Mitt interacts with the NFATc1 pathway. Mitt is known to synergize with NFATc1 on some transcriptional targets shared by Mitf and NFATc1. We will also examine the ability of the two Mitt isoforms in synergizing with NFATc1 on these compound transcriptional targets. The proposed project will allow us to unravel the osteoclast-specific role of Mitt in osteoclastogenesis and to determine which isoform is responsible in assisting NFATc1 to master osteoclast differentiation.