MT1-MMP modulates the mechanosensitivity of osteocytes.
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.
Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Department of Oral Cell Biology, Research Institute MOVE, Amsterdam, The Netherlands.
Rishikesh N
RN
Kulkarni
Astrid D
AD
Bakker
Elisabeth V
EV
Gruber
Thomas D
TD
Chae
Joris B B
JB
Veldkamp
Jenneke
J
Klein-Nulend
Vincent
V
Everts
D000818:Animals; D022001:Focal Adhesions / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010011:Osteocytes / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D011673:Pulsatile Flow; D034741:RNA, Small Interfering / Q000235:genetics; D013314:Stress, Mechanical
D034741:RNA, Small Interfering; D053511:Matrix Metalloproteinase 14