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Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA. (Translational Research 2020; 215:1À16) Abbreviations: ALP = alkaline phosphatase; ARS = Alizarin Red Staining; BCIP = 5-bromo-4-chloro-3indolyl-phosphate; cDNA = complementary DNA; CCK-8 = Cell Counting Kit 8; CM = conditioned medium; CPC = cetylpyridinium chloride solution; CT = computed tomography; DAPI = 4 0 ,6-diamidino-2-phenylindole; DMEM = Dulbecco's modified Eagle's medium; ECMP = extracellular matrix protein; EDTA = ethylenediaminetetraacetic acid; EdU = 5-ethynyl-2 0 -deoxyuridine; ELISA = enzyme-linked immunosorbent assay; FBS = fetal bovine serum; FITC = fluorescein isothiocyanate; GH = growth hormone; GHPA = growth hormone-secreting pituitary adenoma; HE = hematoxylin and eosin; HRCT = high-resolution computed tomography; IGF-1 = insulin-like growth factor-1; IHC = immunohistochemistry; miRNA = microRNA; MVB = microvesicular bodies; NBT = nitro-blue-tetrazolium; NFPA = nonfunctioning pituitary adenoma; OCN = osteocalcin; PBS = phosphate-buffered saline; PCNA = proliferating cell nuclear antigen; PROB = primary rat osteoblast; qRT-PCR = quantitative real-time polymerase chain reaction; RT = room temperature; SD = standard deviation; siRNA = small-interfering RNA; TSG101 = tumor-susceptibility gene 101This study provides evidence that exosomal miR-21 derived from GHPA cells can manipulate osteoblast proliferation, osteocalcin and collagen I synthesis, and bone formation through a pathway distinct from the traditional GH/IGF-1 axis. This finding may serve as a foundation for developing new therapeutics that target GHPA.