Loss of , an Arthrogryposis Multiplex Congenita Associated Gene, Promotes Osteoclastogenesis in Mice.

encodes a -type zinc finger protein, mutations of which lead to a spectrum of diseases known as associated rare disorders (ZARD). In addition to neurological phenotypes, the most typical symptoms of ZARD are multiple joint contractures of varying degrees, accompanied by abnormal development of muscles and bones, and osteoporosis in some cases. The pathogenic mechanisms of such bone related phenotypes, however, remain unclear. Here, we showed that is expressed in the developing bones in mice. knockout mice were neonatal-lethal and smaller in size, with reduced calcification of long bones. Upon induced loss of postnatally, the femoral bones developed an osteoporosis-like phenotype, with reduced bone mineral density, bone-volume fraction, and trabecular bone number. Knockdown of showed no clear effect on the expression of osteogenic differentiation genes in in vitro models using mesenchymal stem cells. Interestingly, knockdown significantly enhanced osteoclast differentiation and bone resorption in induced bone marrow-derived macrophages. We further confirmed that the number of osteoclasts in the long bone of knockout mice was increased, as well as the expression of the serum bone resorption/osteoporosis marker CTX-1. Our study unveils a new role of in osteoclast differentiation and bone development, providing new clues on the pathology of ZARD.