MT1-MMP modulates the mechanosensitivity of osteocytes

Article (PDF Available)inBiochemical and Biophysical Research Communications 417(2):824-9 · December 2011with21 Reads
DOI: 10.1016/j.bbrc.2011.12.045 · Source: PubMed
Membrane-type matrix metalloproteinase-1 (MT1-MMP) is expressed by mechanosensitive osteocytes and affects bone mass. The extracellular domain of MT1-MMP is connected to extracellular matrix, while its intracellular domain is a strong modulator of cell signaling. In theory MT1-MMP could thus transduce mechanical stimuli into a chemical response. We hypothesized that MT1-MMP plays a role in the osteocyte response to mechanical stimuli. MT1-MMP-positive and knockdown (siRNA) MLO-Y4 osteocytes were mechanically stimulated with a pulsating fluid flow (PFF). Focal adhesions were visualized by paxillin immunostaining. Osteocyte number, number of empty lacunae, and osteocyte morphology were measured in long bones of MT1-MMP(+/+) and MT1-MMP(-/-) mice. PFF decreased MT1-MMP mRNA and protein expression in MLO-Y4 osteocytes, suggesting that mechanical loading may affect pericellular matrix remodeling by osteocytes. MT1-MMP knockdown enhanced NO production and c-jun and c-fos mRNA expression in response to PFF, concomitantly with an increased number and size of focal adhesions, indicating that MT1-MMP knockdown osteocytes have an increased sensitivity to mechanical loading. Osteocytes in MT1-MMP(-/-) bone were more elongated and followed the principle loading direction, suggesting that they might sense mechanical loading. This was supported by a lower number of empty lacunae in MT1-MMP(-/-) bone, as osteocytes lacking mechanical stimuli tend to undergo apoptosis. In conclusion, mechanical stimulation decreased MT1-MMP expression by MLO-Y4 osteocytes, and MT1-MMP knockdown increased the osteocyte response to mechanical stimulation, demonstrating a novel and unexpected role for MT1-MMP in mechanosensing.
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    • "It is plausible that MMP14 is activated downstream of stretchactivated Ca þ2 channels which are known to be active in these cells (Lee et al., 1999). This conjecture is supported by the fact that there is a greater intensity of MMP14 immunostaining in stretched cells which are in the process of detaching from the cell sheet and is consistent with recent data describing a role for MMP14 in mechanosensitivity of osteocytes (Kulkarni et al., 2012). At this point, without a commercially available small molecule inhibitor specific for MMP14, we are unable to make a more definitive conclusion as to the precise role of MMP14. "
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    • "It was found that mechanical stimulation by means of a pulsatile fluid flow induced stabilization of β-catenin in osteocytes in a FAK-dependent mechanism [69]. Interestingly, knockdown of membrane-type matrix metalloproteinase-1 (MT1-MMP) increased the number and size of focal adhesions in cultured MLO-Y4 osteocytes concomitantly with an enhanced NO production and c-jun and c-fos mRNA expression in response to mechanical stimulation [70]. This indicates that MT1-MMP knockdown osteocytes have an increased sensitivity to mechanical loading and demonstrates a novel and unexpected potential role for MT1-MMP in mechanosensing. "
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    • "Of the three types of cells comprising bone, osteocytes are the most abundant, making up 95% of all cells in bone ([3] and references therein), yet little is known of osteocyte biology and function. Recent studies have begun to elucidate the role of osteocytes in bone formation, bone function, bone maintenance and bone pathology [4] [5] [6] [7] [8] [9] [10] [11] [12], but many questions regarding the fundamental biology of these cells remain. Issues that are still poorly understood include: 1) the potential variation in the morphology of osteocytes in bones with different origins (intramembranous vs endochondral) and their different roles in vertebrate body plans, (e.g., do osteocytes function differently in long bones vs bony flat plates); 2) what temporal limits exist on osteocyte preservation in the bony matrix, and whether preservation is dependent on taxon, bone type, geologic time, depositional environment or other factors; and 3) if these cells persist and can be shown to be endogenous to the organisms, can chemical/molecular analyses of these remnants shed light on the physiology, phylogeny, and/or ecology of extinct organisms across geological time. "
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