C-reactive　protein　(CRP)　is　an　established　marker　of　rheumatoid　arthritis　(RA)　but　with　ill-defined　actions　in　the　pathogenesis.　Here,　we　show　that　CRP　regulates　the　differentiation　of　osteoclasts,　a　central　mediator　of　joint　inflammation　and　bone　erosion　in　RA,　in　a　conformation-and　receptor　activator　of　NF-kappa　B　ligand　(RANKL)-dependent　manner.　CRP　in　the　native　conformation　is　ineffective,　whereas　the　monomeric　conformation　(mCRP)　actively　modulates　osteoclast　differentiation　through　NF-kappa　B　and　phospholipase　C　signaling.　Moreover,　mCRP　can　bind　RANKL,　the　major　driver　of　osteoclast　differentiation,　and　abrogate　its　activities.　The　binding　and　inhibition　of　RANKL　are　mediated　by　the　cholesterol　binding　sequence　(CBS)　of　mCRP.　Corroborating　the　in　vitro　results,　CRP　knockout　exacerbates　LPS-induced　bone　resorption　in　mice.　These　results　suggest　that　mCRP　may　be　protective　in　joint　inflammation　by　inhibiting　pathological　osteoclast　differentiation　and　that　the　CBS　peptide　could　be　exploited　as　a　potential　RANKL　inhibitor.