Masafumi Fukagawa, M.D., Ph.D., FJSIM
Associate Professor and Chief
Division of Nephrology and Dialysis Center
Kobe University School of Medicine
Recently, mechanisms of osteoclastogenesis and osteoclast activation have been intensively elucidated at molecular levels (2). Three different classes of humoral factors promote osteoclastogenesis, which include active vitamin D and its analogues, hormones or cytokines. Although these humoral factors bind to osteoblasts in an independent manner, they eventually induce the expression of a membrane bound glycoprotein on the cell surface. This membrane bound glycoprotein is called osteoclast differentiation factor (ODF), which is identical molecule to RANKL, TRANCE, or OPGL. When ODF binds to its ligand (RANK) expressed on the surface of osteoclast precursor cells, they start differentiation into mature osteoclasts. These actions of ODF on osteoclastic lineage result in increased bone resorption. Thus, disturbance of any of these steps can be responsible for the skeletal resistance to PTH in uremia.
The first possibility is that effects of humoral factors that promote ODF expression other than PTH might be disturbed. Since 1,25-dihydroxyvitamin D is one of such factors, this mechanism should be involved at least in part. Supporting such a possibility, disturbance of vitamin D action by uremic toxins has been demonstrated by Hsu et al. However, as well known, administration of active vitamin D sterols cannot fully normalize skeletal resistance to PTH in uremia indicating that the shortage of calcitriol does not play major roles.
Next possibility is that PTH activity to induce ODF might be insufficient$B!%(B Recently, a new assay of PTH that recognizes only whole molecule of PTH (1-84 PTH) has been established. Because of the recognition site of the antibody, conventional intact PTH assay recognizes fragments of 7-84 PTH as well as whole molecule of 1-84 PTH. Plasma concentration of PTH detected by this 'whole PTH assay' was much lower than that by 'intact PTH assay'. More interestingly, 7-84 fragment of PTH, which is recognized by 'intact PTH assay', but not by 'whole PTH assay', competitively inhibits the action of 1-84 PTH (3). Thus, in uremia, it may be possible that PTH concentration is overestimated, and that its fragments further suppress the action of PTH. In addition, the pathway from binding to PTH receptor to ODF expression in osteoblasts might be interfered. It has been suggested that PTH-I receptor expression in osteoblasts is down-regulated in uremic patients, but still controversial. PTH receptor signaling pathway may be also disturbed in uremia, which possibility remains to be elucidated.
Another possible mechanism is the disturbance of the steps after induction of ODF. Osteoprotegerin (OPG), also called osteoclatogenesis inhibitory factor (OCIF), is a decoy receptor for ODF. Our preliminary study suggested that this OPG accumulates in serum as renal function declines (4). In chronic dialysis patients, serum concentration of OPG reaches 3 to 5 times of normal that would inhibit 50% of osteoclastogenesis in vitro. Thus, it may be possible that accumulated OPG inhibits osteoclastogenesis in uremic patients. Disturbance of other steps after the induction of ODF in uremia needs to be studied more intensively in near future.
1. Massry SG, Coburn JW, Lee DB, Jowsey J, Kleeman CR: Skeletal resistance to parathyroid hormone in renal failure. Studies in 105 human subjects. Ann Intern Med 78: 357-364, 1973
2. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocrine Rev 1999; 20: 345-357.
3. Slatopolsky E, Finch JL, Clay P, Martin D, Sicard G, Singer G, Gao P, Cantor T, Dusso A: A novel mechansiam for skeletal resistance in uremia. Kidney Int 753-761, 2000
4. Kazama JJ, Shigematsu T, Tsuda E, Yano K, Gejyo F, Kawaguchi Y, Kurokawa K, Fukagawa M: Increased circulating osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) in patients with chronic renal failure, J Am Soc Nephrol 10: 599A, 1999 (abstract)