BoneKEy-Osteovision | Commentary
Some light shines on the resorption cavity
DOI:10.1138/2002025
Bone remodeling consists of a number of steps that I might best call “black boxes” - where we describe the event with airy confidence, as though anyone would obviously understand it, so why should we stop to explain? Quite some light has been shed on one of these black boxes by Everts et al. in a January 2002 JBMR paper () in which they applied light and electron microscopy to a number of in vitro models to describe how bone lining cells, aided by matrix metalloproteinases (MMP's), carry out the task of cleaning out resorption pits after osteoclasts complete their task. They then go on to lay down a thin layer of collagen along the Howship's lacuna, closely associated with a cement line. We have always been vague about this process, by which demineralized collagen is removed from resorption cavities - what Everts et al. call ( with perhaps less than felicitous terminology ) “cleaning its bottom” from bone matrix leftovers. Mononuclear cells have been implicated in this function in many studies, sometimes fibroblasts (), but more commonly macrophages ( e.g. ,). What Everts et al. have done is to identify the bone lining cells cytologically at sites of resorption, both in calvaria and long bones, and show that these cells actually engulf the collagen fragments on the bone surface after the osteoclasts have resorbed. As an added feature, they examined resorption lacunae from pycnodysostotic human subjects and from cathepsin K-deficient mice. In each of these cases large amounts of undigested matrix are left remaining after the action of osteoclasts that are inefficient because they lack cathepsin K, but bone lining cells enter the resorption areas after the osteoclasts, and remove the undigested collagen. This approach provided further support for their observations pointing to the central part played in this process by MMP's - most likely matrix-bound, and perhaps activated by the serine proteinase, plasmin, generated through the action of plasminogen activators (PA's)(). An interesting observation that may be quite relevant, is that of Daci et al. (), who in studying the bone phenotype in mice rendered null for urokinase PA and tissue PA (uPA/tPA-/-), found that the only striking aspect of the phenotype was the impairment of non-osteoclast-mediated bone matrix breakdown.
Although remodeling does not take place in mouse bone, the studies on mouse bone by Everts et al. can be extrapolated to the remodeling process, and thereby fill in a number of gaps in our appreciation of these events. It ascribes a central role to cells of the osteoblast lineage - lining cells that are capable of tissue remodeling activity that is specific to the resorption/reversal phase of bone remodeling. This description advances us significantly from the observations of Takahashi et al. (), who identified cells of the osteoblast lineage at sites of bone resorption and showed that they were able to engulf collagen fragments. In order to carry out the tasks described by Everts et al., the cells must use differentiated properties that they acquire and retain as part of the osteoblast lineage. These include particularly the capacity to respond appropriately to the cytokines and growth factors which most likely govern these steps, even though the cells no longer retain the ability of the mature osteoblast to make copious amounts of bone matrix. They can nevertheless make the thin collagen lining of the Howship's lacuna, as well as the osteopontin-rich cement line.
Other phenotypic features of the lineage are implied also from the observations of this study, in that virtually all osteoclasts attached to bone were in close contact with bone lining cells, and furthermore cytoplasmic extensions of these cells contained small vesicles. These could be reflective of signal exchange between lining cells and osteoclasts; they are consistent with the regulation of osteoclast function by cells of the osteoblast lineage (), and presumably the cells produce both RANKL and osteoprotegerin.
Perhaps we should look upon the lining cell with renewed respect and interest. It certainly populates bone in great abundance, lining trabecular and endocortical surfaces. What Everts et al. have done is draw attention in an elegant morphological study to functional roles for the lining cell, contributing to a key stage in the bone remodeling process, one which has not previously been probed in such depth. What these cells appear to be doing at this stage of the osteoblast lineage is carrying out a number of functions directly related to bone breakdown, but nevertheless linked to the process of bone renewal.
For a body of work which is “only” descriptive, it is highly instructive. As it happens in all of science, much of our accumulated wisdom about bone has come to us step by step. There are not many huge leaps, but we move along feeling that we understand a little more than we had before, and this piece of work is a great help. Perhaps we could distinguish between “understanding” on the one hand, and “attainment of explanation” on the other - in this case a careful and critical description of events, without an appreciation of which there can be no understanding. Real understanding will come when, using these observations as a basis, we learn of the signals that instruct cells at remodeling sites to start each of the special tasks, to finish, to move on, and to die.
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