24,25-(OH)(2)D-3 regulates cartilage and bone via autocrine and endocrine mechanisms

The purpose of this paper is to summarize recent advances in our understand ing of the physiological role of 24(R),25(OH)(2)D-3 in bone and cartilage a nd its mechanism of action. With the identification of a target cell, the g rowth plate resting zone (RC) chondrocyte, we have been able to use cell bi ology methodology to investigate specific functions of 24(R),25(OH)(2)D-3 a nd to determine how 24(R),25(OH)(2)D-3 elicits its effects. These studies i ndicate that there are specific membrane-associated signal transduction pat hways that mediate both rapid, nongenomic and genomic responses of RC cells to 24(R),25(OH)(2)D-3. 24(R),25(OH)(2)D-3 binds RC chondrocyte membranes w ith high specificity, resulting in an increase in protein kinase C (PKC) ac tivity. The effect is stereospecific; 24R,25(OH)(2)D-3, but not 248,25(OH)( 2)D-3, causes the increase, indicating a receptor-mediated response. Phosph olipase D-2 (PLD2) activity is increased, resulting in increased production of diacylglycerol (DAG), which in turn activates PKC. 24(R),25(OH)(2)D-3 d oes not cause translocation of PKC to the plasma membrane, but activates ex isting PKC alpha. There is a rapid decrease in Ca2+ efflux, and influx is s timulated. 24(R),25(OH)(2)D-3 also reduces arachidonic acid release by decr easing phospholipase A(2) (PLA(2)) activity, thereby decreasing available s ubstrate for prostaglandin production via the action of cyclooxygenase-1. P GE(2) that is produced acts on the EP1 and EP2 receptors expressed by RC ce lls to downregulate PKC via protein kinase A, but the reduction in PGE(2), decreases this negative feedback mechanism. Both pathways converge on MAP k inase, leading to new gene expression. One consequence of this is productio n of new matrix vesicles containing PKC alpha and PKC zeta and an increase in PKC activity. The chondrocytes also produce 24(R),25(OH)(2)D-3, and the secreted metabolite acts directly on the matrix vesicle membrane. Only PKC zeta is directly affected by 24(R),25(OH)(2)D-3 in the matrix vesicles, and activity of this isoform is inhibited. This effect may be involved in the control of matrix maturation and turnover. 24(R),25(OH)(2)D-3 causes RC cel ls to mature along the endochondral developmental pathway, where they becom e responsive to 1 alpha .25(OH)(2)D-3 and lose responsiveness to 24(R),25(O H)(2)D-3, a characteristic of more mature growth zone (GC) chondrocytes. 1 alpha .25(OH)(2)D-3 elicits its effects on GC through different signal tran sduction pathways than those used by 24(R),25(OH)(2)D-3. These studies indi cate that 24(R).25(OH)(2)D-3 plays an important role in endochondral ossifi cation by regulating less mature chondrocytes and promoting their maturatio n in the endochondral lineage. (C) 2001 Elsevier Science Inc. All rights re served.