Leukemia inhibitory factor/differentiation‐stimulating factor (LIF/D‐factor): Regulation of its production and possible roles in bone metabolism

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Abstract
Leukemia inhibitory factor/differentiation‐stimulating factor (LIF/D‐factor), expression of its mRNA, and possible roles in bone metabolism were studied in murine primary and clonal osteoblast‐like cells. Local bone‐resorbing factors such as IL‐1, TNFα, and LPS strongly induced expression of LIF/D‐factor mRNA in both clonal MC3T3‐E1 cells and primary osteoblast‐like cells. Neither parathyroid hormone nor 1α,25‐dihydroxyvitamin D3 stimulated expression of LIF/D‐factor mRNA. LIF/D‐factor per se did not stimulate expression of its own mRNA. Appreciable amounts of LIF/D‐factor were detected in synovial fluids from rheumatoid arthritis (RA) patients but not in those with osteoarthritis (OA). Simultaneous treatment with LIF/D‐factor, IL‐1, and IL‐6 at the concentrations found in synovial fluids from RA patients greatly enhanced bone resorption, though these cytokines did not stimulate bone resorption when separately applied. This suggests that LIF/D‐factor produced by osteoblasts is in concert with other boneresorbing cytokines such as IL‐1 and IL‐6 involved in the bone resorption seen in the joints of RA patients. LIF/D‐factor specifically bound to MC3T3‐E1 cells with an apparent dissociation constant of 161 pM and 1,100 binding sites/cell. LIF/D‐factor dose‐dependently suppressed incorporation of [3H]thymidine into MC3T3‐E1 cells. In addition, it potentiated the alkaline phosphatase activity induced by retinoic acid, though LIF/D‐factor alone had no effect on enzyme activity. These results suggest that LIF/D‐factor is involved in not only osteoclastic bone resorption but also osteoblast differentiation in conjugation with other osteotropic factors.