The biochemical pathway mediating the proliferative response of bone cells to a mechanical stimulus

被引:95
作者
Brighton, CT [1 ]
Fisher, JRS [1 ]
Levine, SE [1 ]
Corsetti, JR [1 ]
Reilly, T [1 ]
Landsman, AS [1 ]
Williams, JL [1 ]
Thibault, LE [1 ]
机构
[1] UNIV PENN, SCH ENGN & APPL SCI, DEPT BIOENGN, PHILADELPHIA, PA 19104 USA
关键词
D O I
10.2106/00004623-199609000-00007
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
Calvarial bone cells of rats were subjected to either a cyclic biaxial strain of 0.17 per cent (1700 microstrain) or a hydrostatic pressure of 2.5, five, or ten pounds per square inch (17.2, 34.5, or sixty-nine kilopascals). The frequency was held constant at one hertz for both types of mechanical stimulation, When cultured bone cells that had been subjected to a cyclic biaxial strain for two hours were harvested twenty-two hours later, it was found that the level of prostaglandin E(2) had increased significantly (p < 0.01) as had cellular proliferation (p < 0.01), as indicated by the incorporation of [H-3]-thymidine. The addition to the medium of indomethacin, an inhibitor of prostaglandin synthesis, at a ten-micromolar concentration significantly inhibited (p < 0.01) the increase in prostaglandin E(2) synthesis but had no effect on the strain-induced increase in cellular proliferation, as indicated by the incorporation of [H-3]-thymidine, Twenty-four hours after exposure to the same cyclic biaxial strain for thirty seconds, other cultured bone cells showed a significant increase in the level of cytoskeletal calmodulin (p < 0.05) and in the DNA content (p < 0.05), N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), a calmodulin antagonist, was added to the medium at a one-micromolar concentration, which had been shown to have no effect on the increase in the DNA content of control cells; W-7 completely blocked the increase in the level of cytoskeletal calmodulin and in the DNA content in the cells that were subjected to a cyclic biaxial strain, The bone cells subjected to a hydrostatic pressure showed a dose-dependent increase in the concentration of cytosolic Ca2+, as measured with Fura 2-AM, a fluorescent indicator of intracellular calcium, With a pressure of ten pounds per square inch (sixty-nine kilopascals), the increase in the concentration of cytosolic Ca2+ was nearly eight times greater than that at 2.5 pounds per square inch (17.2 kilopascals) (126 +/- 15.2 compared with 16 +/- 8.0 nanomolar, mean and standard deviation), The addition to the medium of neomycin, an inhibitor of the inositol phosphate cascade, at a ten-millimolar concentration completely blocked the increase in the concentration of cytosolic Ca2+ in these cells; this concentration of neomycin had been shown to have no effect on proliferation in control bone cells, There was also a dose-dependent relationship between the duration of the stimulus and the cellular proliferation, Remarkably, one cycle of pressure at ten pounds per square inch (sixty-nine kilopascals) and a frequency of approximately one hertz produced a 57 per cent increase in the incorporation of [H-3]-thymidine at twenty-four hours (p < 0.001), From these findings, we hypothesized that the inositol phosphate cascade-cytosolic Ca2+-cytoskeletal calmodulin system plays a dominant role in the signal transduction of a mechanical stimulus into increased proliferation of bone cells, at least under the conditions reported here, CLINICAL RELEVANCE: Understanding the mechanisms by which bone cells convert a mechanical signal into a biological response is the beginning of an understanding of Wolff's law which states that form follows function, A complete understanding of Wolff's law eventually should lead to an understanding of the cellular and molecular processes governing bone-remodeling and may allow therapeutic manipulation of bone-remodeling in clinical practice.
引用
收藏
页码:1337 / 1347
页数:11
相关论文
共 64 条
[21]   NEW ASPECTS OF MODE OF ACTION OF NONSTEROID ANTIINFLAMMATORY DRUGS [J].
FERREIRA, SH ;
VANE, JR .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1974, 14 :57-73
[22]  
FITZPATRICK FA, 1988, PHARMACOL REV, V40, P229
[23]   CALCIUM SIGNALING IN NEURONS - MOLECULAR MECHANISMS AND CELLULAR CONSEQUENCES [J].
GHOSH, A ;
GREENBERG, ME .
SCIENCE, 1995, 268 (5208) :239-247
[24]  
HANSEN M, 1993, J CELL SCI, V106, P995
[25]  
HARELL A, 1977, CALC TISS RES, V22, P202
[26]   MECHANICAL STRETCHING INCREASES THE NUMBER OF CULTURED BONE-CELLS SYNTHESIZING DNA AND ALTERS THEIR PATTERN OF PROTEIN-SYNTHESIS [J].
HASEGAWA, S ;
SATO, S ;
SAITO, S ;
SUZUKI, Y ;
BRUNETTE, DM .
CALCIFIED TISSUE INTERNATIONAL, 1985, 37 (04) :431-436
[27]   EFFECTS OF ORALLY-ADMINISTERED PROSTAGLANDIN E-2 ON CORTICAL BONE TURNOVER IN ADULT DOGS - A HISTOMORPHOMETRIC STUDY [J].
HIGH, WB .
BONE, 1987, 8 (06) :363-373
[28]   PROSTAGLANDIN-E2 ENHANCES CORTICAL BONE MASS AND ACTIVATES INTRACORTICAL BONE REMODELING IN INTACT AND OVARIECTOMIZED FEMALE RATS [J].
JEE, WSS ;
MORI, S ;
LI, XJ ;
CHAN, S .
BONE, 1990, 11 (04) :253-266
[29]   THE EFFECTS OF PROSTAGLANDIN-E2 IN GROWING-RATS - INCREASED METAPHYSEAL HARD TISSUE AND CORTICO-ENDOSTEAL BONE-FORMATION [J].
JEE, WSS ;
UENO, K ;
DENG, YP ;
WOODBURY, DM .
CALCIFIED TISSUE INTERNATIONAL, 1985, 37 (02) :148-157
[30]   BIOCHEMICAL SIGNAL TRANSDUCTION OF MECHANICAL STRAIN IN OSTEOBLAST-LIKE CELLS [J].
JONES, DB ;
NOLTE, H ;
SCHOLUBBERS, JG ;
TURNER, E ;
VELTEL, D .
BIOMATERIALS, 1991, 12 (02) :101-110