Host-Derived Matrix Metalloproteinase-13 Activity Promotes Multiple Myeloma-Induced Osteolysis and Reduces Overall Survival.
Cancer Res
; 81(9): 2415-2428, 2021 05 01.
Article
in En
| MEDLINE
| ID: mdl-33526510
ABSTRACT
Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal-derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13-null mice. In independent in vivo studies, MMP13-null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed. Ex vivo stromal coculture assays showed reduced formation and activity in MMP13-null osteoclasts. Analysis of soluble factors from wild-type and MMP13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. SIGNIFICANCE:
Genetic and pharmacologic approaches show that bone stromal-derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/81/9/2415/F1.large.jpg.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Osteolysis
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Signal Transduction
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Matrix Metalloproteinase 13
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Multiple Myeloma
Type of study:
Prognostic_studies
Limits:
Animals
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Female
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Humans
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Male
Language:
En
Journal:
Cancer Res
Year:
2021
Type:
Article