Intercellular Adhesion Molecule 1 Discriminates Functionally Different Populations of Human Osteoblasts: Characteristic Involvement of Cell Cycle Regulators

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Abstract
The concept of differential regulation of certain adhesion molecules on different cell subsets and their relevance to cell functions has emerged in recent years. The initial event in bone remodeling is an increase in osteoclastic bone resorption and cell adhesion between osteoclastic precursors and bone marrow stromal cells or osteoblasts is known to commit the osteoclast development. Here, we show that human osteoblasts can be divided into two subsets based on the expression of the intercellular adhesion molecule (ICAM)‐1; ICAM‐1+ osteoblasts highly adhered to monocytes, including osteoclast precursors, produced osteoclast differentiation factor (ODF), and induced multinuclear osteoclast‐like cell formation. Anti‐ODF monoclonal antibody (mAb) did not inhibit the adhesion of monocytes to osteoblastic cells, whereas anti‐leukocyte function‐associated antigen (LFA)‐1, a receptor for ICAM‐1, mAb blocked the adhesion. We thereby propose that the higher affinity adhesion via LFA‐1/ICAM‐1 is prerequisite for efficient function of membrane‐bound ODF during osteoclast maturation. The functional characteristics of ICAM‐1+ osteoblasts were emphasized further by cell cycle regulation, as manifested by (i) up‐regulation of p53 and p21, (ii) reduction of activity of cyclin‐dependent kinase (cdk) 6, (iii) underphosphorylation of retinoblastoma protein, (iv) increased Fas but reduced bcl‐2 expression, and (v) majority of cells remained at G0/G1 phase. Furthermore, ICAM‐1+ osteoblasts were induced by interleukin‐1β (IL‐1β). Taken together, we propose that the differentiation of osteoblasts to ICAM‐1+ subpopulation by inflammatory cytokines plays an important role in osteoporosis, which is observed in patients with chronic inflammation, because ICAM‐1+ osteoblasts can bias bone turnover to bone resorption, committing osteoclast maturation through cell adhesion with its precursor, and the majority of ICAM‐1+ osteoblasts arrested at G0/G1 phase. Such regulation of cell cycle arrest also is an important determinant of the life span of cells in bone in which continuous bone remodeling maintains its homeostasis.

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