The cellular basis of bone remodeling: The quantum concept reexamined in light of recent advances in the cell biology of bone

SummaryThe cellular basis of the normal bone remodeling sequence in the human adult is discussed in relation to a cycle of five stages—quiescence, activation, resorption, reversal, formation, and return to quiescence. Normally, 80% or more of free bone surfaces are quiescent with respect to remodeling. The structure of the quiescent surface comprises 5 layers; listed in order out toward the bone marrow these are: the lamina limitans (the electron dense outer edge of the mineralized bone matrix), unmineralized connective tissue that may be confused with osteoid by light microscopy, flattened lining cells of osteoblast lineage separated by narrow gaps, more unmineralized connective tissue, and finally either the squamous sac cells of red marrow or the cytoplasm of fat cells of yellow marrow. Activation requires the recruitment of new osteoclasts derived from precursor cells of the mononuclear phagocyte system (and so ultimately from the hematopoietic stem cell), a method for precursor cells to penetrate the cellular and connective tissue barrier of the quiescent surface, and so gain access to the bone mineral, and mechanisms for their attraction and binding to the mineralized surface, possibly in response to chemotactic signals released from bone matrix or mineral. Each of these three steps is probably mediated in some way by lining cells. Resorption is carried out by osteoclasts, most of which are multinucleated. The mean life span of individual nuclei is about 12.5 days; the additional nuclei needed to sustain resorption may be derived fromlocal as well as blood-bone precursors, but nothing is known of their fate. Mononuclear cells may participate not only as precursor cells but as additional resorbing cells, helper cells, and releasers of osteoclast-stimulating agents such as prostaglandins or OAF. It is not known how the size, shape and depth of resorption cavities are controlled, but termination of resorption may involve the release of a suppressor agent (such as prostacyclin) by osteocytes and/or lining cells. During the reversal period the resorption cavity is smoothed off and cement substance is deposited, but the responsible cells are unknown. Successful coupling of formation to resorption requires the proliferation and differentiation of osteoblast precursor cells, focal accumulation of the new osteoblasts within the resorption cavity, and their alignment as a continuous monolayer of uniform polarity. These processes are probably mediated by growth factors released during resorption, and by chemotactic agents present in the bone matrix or in the cement substance. Formation of new bone within the resorption cavity begins with rapid matrix apposition followed some days later by the onset of mineralization. Although the average rates of these two processes during the life span of the osteoid seam (the layer of unmineralized bone matrix) are the same, their instantaneous rates are systematically out of step, so that the osteoid seam width increases rapidly to a maximum of about 20 µm and then declines progressively. At each point on the surface a single osteoblast makes all the bone matrix that is formed, and how completely the cavities are refilled probably depends more on the number of osteoblasts initially assembled than on their individual activity. At the termination of matrix synthesis, mineralization continues more slowly until the osteoid seam eventually disappears and the cells remaining on the surface complete their morphologic and functional transformation to lining cells. The surface has now returned to its original state of quiescence except that the bone is younger. How the remodeling sequence just described is modified to accomplish structural change in response to altered mechanical load is unclear; in particular, it is not known whether there can be direct transformation of a quiescent to a forming surface without intervening resorption.