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Hematopoiesis in mice is extremely resilient to wide variation in TIMP/MMP balance
Peter Haviernik1, Maria T Diaz, Eleonora Haviernikova
1Department of Medicine, Division of Hematology-Oncology, Case Western Reserve University, Cleveland, OH 44106, USA.
Abstract:
Tissue inhibitors of matrix metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) and are associated with normal and pathologic extracellular matrix turnover. Because the microenvironment is critical for normal hematopoietic stem/progenitor cell function, we aimed to determine whether alterations in the TIMP/MMP balance impact upon normal hematopoiesis in mice. We have used both overexpression and knockout mouse models to determine whether early hematopoiesis is susceptible to potentially pathologic changes in TIMP/MMP level. These studies used TIMP-1(-/-) mice and retroviral vectors co-expressing human TIMP-1 or TIMP-2 linked with the green fluorescent protein (GFP) transduced into bone marrow (BM) cells and transplanted into lethally-irradiated recipient mice. Loss of TIMP-1 in knockout mice or retroviral overexpression of TIMP-1 or TIMP-2 did not alter hematopoietic stem/progenitor function during steady-state hematopoiesis. Surprisingly, even when applying hematopoietic stress through mobilization, chemotaxis, or myelosuppression, murine hematopoiesis was not adversely affected by TIMP-1 or TIMP-2 level. We conclude that TIMP/MMP balance alone does not exert significant influence on blood cell development and homeostasis. An important corollary of these studies is that specific modulation using MMP inhibitors for cancer or immunologic therapy is unlikely to have adverse hematopoietic side effects.
Insights
Altering levels of tissue inhibitors of matrix metalloproteinases (TIMPs) did not affect blood cell development in mice. This suggests MMP inhibitors are unlikely to cause adverse hematopoietic side effects in therapies.
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Tissue inhibitors of matrix metalloproteinases (TIMPs) regulate extracellular matrix turnover.
- The bone marrow microenvironment is crucial for hematopoietic stem/progenitor cell function.
- The impact of TIMP/MMP balance on hematopoiesis remains unclear.
Purpose of the Study:
- To investigate the role of TIMP/MMP balance in murine hematopoiesis.
- To determine if altered TIMP levels affect hematopoietic stem/progenitor cell function.
- To assess potential adverse hematopoietic side effects of MMP inhibitor therapies.
Main Methods:
- Utilized TIMP-1 knockout mice.
- Employed retroviral vectors for TIMP-1 and TIMP-2 overexpression in bone marrow cells.
- Transplanted genetically modified bone marrow cells into irradiated recipient mice.
- Evaluated hematopoietic function under steady-state and stressed conditions (mobilization, chemotaxis, myelosuppression).
Main Results:
- Loss of TIMP-1 did not impair steady-state hematopoiesis.
- Overexpression of TIMP-1 or TIMP-2 did not affect hematopoietic stem/progenitor function.
- Hematopoiesis remained unaffected even under hematopoietic stress.
- Murine blood cell development and homeostasis were not significantly influenced by TIMP/MMP balance.
Conclusions:
- TIMP/MMP balance alone does not significantly impact blood cell development and homeostasis.
- Modulation of MMPs is unlikely to cause adverse hematopoietic side effects.
- These findings support the safety of MMP inhibitors in therapeutic applications.
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