Osteoporosis(OP),one of the most prevalent chronic progressive bone diseases,is caused by deficiency in bone formation by osteoblasts or excessive bone resorption by osteoclasts and subsequently increases the risk of bone fractures.Emerging evidence has indicated that long noncoding RNAs(lncRNAs)play key roles in many biological processes and various disorders.However,the role and mechanism of HOX antisense intergenic RNA myeloid 1(HOTAIRM1),a myeloid-specific IncRNA,in osteoclast differentiation,osteogenic differentiation,and OP remain unclear.In this study,we found that HOTAIRM1 was upregulated during ossification of ligamentum flavum and osteogenic differentiation,while it was downregulated in osteoclast differentiation and in the bone and serum of human and mouse with OP.Further investigation revealed that silencing Hotairml decreased the expression of the osteogenic markers and attenuated osteogenesis.More-over,forced Hotairml expression inhibited the expressions of the osteoclastogenesis markers and alleviated receptor activator of nuclear factor kappa B(NF-κB)ligand(RANKL)-induced osteo-clast differentiation.Mechanically,Hotairml repressed the phosphorylation of p65 and inhibitor of κBα(IκBα)and attenuated RANKL-mediated enhancement of phos-p65 and IκBα,suggesting that Hotairml inhibits RANKL-induced osteoclastogenesis through the NF-κB pathway.In conclu-sion,our data identified a crucial role of HOTAIRM1 in OP,providing a proof of this molecule as a potential diagnostic marker and a possible therapeutic target against OP.