In the present study, the inhibitory effects of ZOL on SOCS1 expression were first confirmed in RAW264.7 cells. In conclusion, our data strongly suggest that onset mechanism of BRONJ is due to the dysregulation of the inflammatory cytokine output with ZOL. The nuclear receptor superfamily consists of 48 members in humans and 49 in mice. Small heterodimer partner is an orphan nuclear receptor that is unique in lacking the DNA binding domain commonly seen in other NRs. Structurally, SHP contains an N-terminal domain, an interaction domain and a repression domain. Functionally, SHP is pleiotropic receptor that plays critical roles in several metabolic diseases, including disorders of bile acid homeostasis, lipid metabolism in adipose tissue and liver, and Toll-like receptor signaling. The action of SHP is through its repression of a complex set of genes in multiple pathways. Recent studies provide strong evidence for a tumor suppressor function of SHP in liver cancer. Specifically, deletion of the Shp gene promoted spontaneous hepatoma formation in mice, and overexpression of Shp inhibited hepatocyte proliferation and activated hepatocyte apoptosis. SHP expression was also markedly diminished in human HCC specimens due to promoter hypermethylation. The newly identified role of SHP in the regulation of DNA methylation raised the intriguing possibility of using SHP as a potential therapeutic target. Apoptosis is essential for maintenance of tissue homeostasis and depends on the activation of caspases, which is tightly regulated by the B-cell lymphoma protein 2 family of proteins. The Bcl2 family contains three functional subgroups, namely the sensors, guardians, and effectors. Bcl2, the founding member of the family, is localized to the membrane surface of the mitochondria, ER, and nucleus. Bcl2 is an antiapoptotic family member containing four conserved a-helical motifs known as Bcl2 homology domains, as well as a transmembrane domain. We recently discovered a cytoplasmic function of SHP in the induction of apoptosis via its interaction with Bcl2 in mitochondria to induce cytochrome c release. However, the specific mitochondrial location of SHP remains elusive. In addition, the detailed interaction domains between SHP and Bcl2 have not been characterized. The nuclear receptor hepatocyte nuclear factor 4 alpha is a key regulator of pathways associated with various metabolic diseases. The AF2 surface of HNF4a in the Cterminal region was reported to interact with SHP based on mammalian two-hybrid mapping. Nonetheless, the domain that is critical for SHP nuclear translocation via its interaction with HNF4a remains to be identified. Using biochemical and molecular biological approaches, we demonstrate in the present study that SHP is localized to the mitochondrial outer membrane. We further show that the interaction domain of SHP and the TM domain of Bcl2 are critical for their protein.