Adult human bone marrow stromal cells regulate expression of their MMPs and TIMPs in differentiation type-specific manner

Abstract

Previously, we described a profound impact of structural conformation of collagen matrix on osteogenic and adipogenic differentiation of bone marrow stromal cells. Thus, a marginal p38-independent adipogenesis on native collagen I matrix contrasts with an efficient p38-dependent differentiation on denatured collagen I. An efficient Hsp90-dependent osteogenesis occurs on native collagen I matrix but not on its denatured counterpart where it is insignificant and proceeds in an Hsp90-independent manner. Whereas only marginal osteogenesis and no detectable adipogenesis of bone marrow stromal cells occur on native collagen IV, the same matrix supports a highly efficient adipogenesis in denatured structural state. The present study addresses the opposite direction in the flow of cell-matrix interaction, namely the cells' influence on structural state of collagen matrix, and tests the possibility that differentiating bone marrow stromal cells may adjust the expression phenotype of MMP and TIMP in such a way that, if translated into matrix modification, would facilitate the maintenance of collagen matrix in or its modification into structural state optimal for the ongoing differentiation process. The results obtained indicate that this is indeed the case. In bone marrow stromal cells stimulated to undergo adipogenesis the expression of MMP increases and that of TIMP decreases. In cells induced to undergo osteogenesis the opposite is true: MMP/TIMP expression is adjusted in a manner that, if translated into matrix modification, could promote the native structural conformation optimal for this type of differentiation. The results obtained also indicate that the observed adjustment in MMP/TIMP expression phenotype might be an early differentiation event and that differentiation stimulation alone might be sufficient to trigger it even on matrices not favorable to a given type of differentiation. The findings of the present study raise significant questions and indicate directions for further experimentation.

Figure 1.. During adipogenic stimulation of bone marrow stromal cells on both native and denatured collagen I matrices the expression of MMP increases and that of TIMP decreases.

C: untreated controls; AD: adipogenic stimuli; NC: native collagen I matrix; DC: denatured collagen I matrix; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase. [*= p<0.05]: significantly different in comparison to the same values in untreated controls.

Figure 2.. Levels of MMP increase and of TIMP decrease during adipogenic differentiation of bone marrow stromal cells on denatured collagen IV matrix.

DCIV: denatured collagen IV matrix; AD: adipogenic stimuli; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase. [*= p<0.05]: significantly different in comparison to the same values in untreated controls.

Figure 3.. Levels of MMP decrease and of TIMP increase during osteogenic differentiation of bone marrow stromal cells on both native and denatured collagen I matrices.

C: untreated controls; OS: osteogenic stimuli; NC: native collagen I matrix; DC: denatured collagen I matrix; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase. [*= p<0.05]: significantly different in comparison to the same values in untreated controls.