Intercellular adhesion molecule 1 discriminates functionally different populations of human osteoblasts: Characteristics involvement of cell cycle regulators

The concept of differential regulation of certain adhesion molecules on dif ferent cell subsets and their relevance to cell functions has emerged in re cent years. The initial event in bone remodeling is an increase in osteocla stic 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 s ubsets based on the expression of the intercellular adhesion molecule (ICAM )-1; ICAM-1(+) osteoblasts highly adhered to monocytes, including osteoclas t 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, wher eas anti-leukocyte function-associated antigen (LFA)-1, a receptor for ICAM -1, mAb blocked the adhesion. We thereby propose that the higher affinity a dhesion 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 retinobla stoma protein, (iv) increased Fas but reduced bcl-2 expression, and (v) maj ority of cells remained at G(0)/G(1) phase. Furthermore, ICAM-1(+) osteobla sts were induced by interleukin-1 beta (IL-1 beta). Taken together, we prop ose that the differentiation of osteoblasts to ICAM-1(+) subpopulation by i nflammatory cytokines plays an important role in osteoporosis, which is obs erved in patients with chronic inflammation, because ICAM-1(+) osteoblasts can bias bone turnover to hone resorption, committing osteoclast maturation through cell adhesion with its precursor, and the majority of ICAM-1(+) os teoblasts arrested at G(0)\G(1) phase. Such regulation of cell cycle arrest also is an important determinant of the life span of cells in bone in whic h continuous bone remodeling maintains its homeostasis.