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Ziouti Fani, Azeem Muhammad, Rummler Maximilian, Rosolowski Maciej, Zapata Gerardo, Rindt Wyonna, Julien Catherine, Tauer Josephine T, Cheng Wen-Hui, Beck Susanne, Seckinger Anja, Hose Dirk, Leich Ellen, Bogen Bjarne, Lynch Maureen E, Kuric Martin, Krug Melanie, Ebert Regina, Zaucke Frank, Jakob Franz, Willie Bettina M, Jundt Franziska
Аннотация
Оригинал публикации
Myeloma engraftment suppresses osteocytic ossification signatures rescued by loading in mice and reveals predictors of patient outcome.
Multiple myeloma (MM) is a malignant plasma cell disease inducing osteolytic lesions by disrupting bone homeostasis, fostering catabolic and suppressing anabolic functions. While the impact on osteoblast generation and function is well documented, alterations of osteocyte function and extracellular matrix (ECM) are not yet fully understood. Thus, using a syngeneic mouse model of MM by injecting MOPC315.BM cells intratibially into BALB/c mice (n = 95), we performed transcriptomic profiling of an osteocyte-enriched population and identified a mechanosensitive matrisomal gene signature, which was disrupted by tumor engraftment. Non-invasive tibial loading restored the expression of 94 ECM-associated genes, including collagens, fibronectin, and aggrecan. Cross-species integration with RNA-sequencing data from 387 MM patients revealed eight ECM-related genes whose expression correlated with overall survival (VEGFA, BCAN, FGF13, TNFSF8, SDC1, LAMC1, SEMA3A, and CCL2). Four of these genes (Vegfa, Sdc1, Sema3a, Ccl2) were also load-responsive in a murine osteocyte (IDG-SW3 cells) bioreactor model. Our findings indicate that an existing mechanosensitive osteocytic repair program is suppressed by MM cells, which can be reinvigorated via a brief single loading session. It suggests that exercise-based interventions may be beneficial to restore bone mass through endochondral ossification programs in patients with MM.