title: Inhibition of mTOR and HIF pathways diminishes chondro-osteogenesis and cell proliferation in chondroblastoma.
abstract: Chondroblastoma (CBL) is a benign bone tumor occurring mostly in teenagers. Despite this, CBL can recur and metastasize after curettage, which may impede normal epiphysis. In search of a novel targeted therapy for CBL, we aimed at BMP-2, a factor critical for chondro-osteogenesis and chondrocyte proliferation. Two pathways upstream of BMP-2, the mTOR and HIF, were targeted with rapamycin (Rapa) and FM19G11 (FM), respectively. Using immunohistochemistry, we found BMP-2 was highly expressed in CBL tissues. CBL cells explanted and confirmed with higher BMP-2 level than normal cartilage. Protumorigenic effect of Rapa and FM on CBL cells were transduced via BMP-2. Combination of Rapa and FM conferred stronger inhibition of cell proliferation than either monotherapy and inhibited levels of chondro-osteogenic markers (Sox9, aggrecan, and type II collagen). To minimize the adverse effect of Rapa, we performed screening in essential amino acids and found leucine deprivation-sensitized CBL cells to Rapa. Combination treatment of low dose Rapa, FM, and leucine deprivation conferred compatible inhibitory effects on CBL cell proliferation, chondro-osteogenic potential, and tumorigenic capacity. We conclude that targeting BMP-2 using mTOR/HIF inhibition could potently curb the disease. Addition of low-leucine diet could lower the dose of rapamycin in chase for less toxicity.
authors.affiliation: Division of Orthopedics, Second People's Hospital of Wuxi, Nanjing Medical University, Wuxi, 214000, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Zheng-jie
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Feng-xiang
authors.initials: FX
authors.lastname: Liu
authors.forename: Ke
authors.initials: K
authors.lastname: Zeng
authors.forename: Ming-quan
authors.initials: MQ
authors.lastname: Qian
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Guo-xing
authors.initials: GX
authors.lastname: Zhu
mesh_terms: D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002804:Chondroblastoma / Q000188:drug therapy*; D020219:Chondrogenesis / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008297:Male; D010012:Osteogenesis / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D046509:Tissue Culture Techniques; D014407:Tumor Cells, Cultured / Q000187:drug effects; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; C525718:BMP2 protein, human; D001549:Benzamides; D055396:Bone Morphogenetic Protein 2; C555528:FM19G11; D051793:Hypoxia-Inducible Factor 1; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D020123:Sirolimus