Rapid vitamin D-dependent PKC signaling shares features with estrogen-dependent PKC signaling in cartilage and bone
Introduction
There is an increasing awareness that steroid hormones initiate rapid cell responses by membrane-associated mechanisms. In our laboratory, we have used a cell culture model that has been particularly valuable for elucidating the underlying mechanisms involved (see [1], [2] for a review). Rat costochondral cartilage growth plate cells are linearly aligned in parallel columns such that the chondrocytes at the top of the growth plate in the resting zone are at a different state of endochondral maturation than cells in the prehypertrophic and upper hypertrophic cell zones (growth zone). Resting zone cells produce a proteoglycan-rich type II collagen extracellular matrix, whereas growth zone cells are preparing their matrix for calcification. Both types of chondrocytes produce extracellular matrix vesicles that contain matrix processing enzymes, but the types of enzymes differ [3]: neutral metalloproteinases dominate in matrix vesicles produced by resting zone cells whereas activity of acid metalloproteinases is higher in matrix vesicles produced by growth zone cells. Matrix vesicles produced by growth zone cells also exhibit higher activity of alkaline phosphatase, which is associated with calcification, and of phospholipases, which are associated with matrix vesicle breakdown and release of matrix processing enzymes into the matrix [4].
Appropriate growth plate development during embryonic skeletal formation and during post-fetal long bone growth, is dependent on steroid hormone regulation. Two of these hormones are critical: vitamin D and estrogen. In the absence of vitamin D, the hypertrophic cell zone expands due to failure of the cartilage to become calcified and rickets results. In the absence of estrogen, growth plates fail to close, resulting in abnormal skeletal development. Clearly, many of the effects of vitamin D and estrogen occur via classical receptor-mediated gene expression. Receptors for 1α,25(OH)2D3 and 17β-estradiol have been identified through specific binding [5], [6], [7], Western blot and by measurement of mRNA levels [8], [9]. Specific binding of radiolabeled 24,25(OH)2D3 [5], [10] has also been reported, although a specific receptor has not been isolated. All three hormones are produced by the cells in a regulated manner [11], [12], resulting in relatively high local levels. In addition, all three hormones cause rapid changes in protein kinase C (PKC) activity [13], [14], suggesting that other membrane-associated pathways are involved.
Section snippets
Activation of PKC
Although 1α,25(OH)2D3, 24R,25(OH)2D3, and 17β-estradiol cause rapid increases in PKC activity in rat costochondral growth plate cartilage cells, there are a number of differences. The effects of 1α,25(OH)2D3 are limited to growth zone cells (Fig. 1A) and peak activity occurs within 9 min [13]. No new gene expression or protein synthesis is required. The effects of 24R,25(OH)2D3 are limited to resting zone chondrocytes (Fig. 1B), but peak activity occurs at 90 min and levels of PKC remain elevated
Summary
Our studies together with those of other laboratories demonstrate the physiological importance of rapid responses to steroid hormones. Growth plate chondrocytes respond to 1α,25(OH)2D3, 24R,25(OH)2D3 and 17β-estradiol in part through pathways initiated by rapid responses. All three hormones mediate their effects through PKC-dependent pathways, but by very different mechanisms. These pathways modulate traditional steroid hormone signaling. In addition, they provide a means for the cells to
Acknowledgements
This work has been supported through grants from the NIH (US PHS DE-05937 and DE-08603), as well as from the Georgia Tech/Emory Center for the Engineering of Living Tissues at the Georgia Institute of Technology in Atlanta, GA.
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