acid-phosphatase and Hypophosphatemia--Familial

The addition of phosphate groups is an essential requirement for the proper functioning of cyclin and cyclin dependent kinase which control various stages in the mitotic division of cancer cells. Thus limiting the availability of phosphate is likely to interfere with the metabolism of rapidly growing malignant cells. The human hormone glucagon and the anti metabolite mithramycin reduce serum phosphate by increasing phosphaturia and are both very effective in treating Paget's disease of bone, a precancerous condition. In this disorder large doses of glucagon given intravenously relieve bone pain and cause serum phosphate and alkaline phosphatase as well as urine hydroxyproline to fall, indicating a marked reduction in bone turnover. A constant iv infusion of glucagon was given to each of three patients all of whom had secondary malignant bone deposits. Two of the patients had primary prostate cancer and one had a squamous cell lung tumour. All three patients had relief of bone pain and a fall in serum alkaline phosphatase. Serum acid phosphatase also fell in the two patients with prostate cancer. It is proposed that the marked drop in serum phosphate due to glucagon causes intracellular phosphate to fall. This in turn disrupts the addition and removal of phosphate groups essential for the proper functioning of cyclin and cyclin dependent kinase. These two proteins control the transition from G1 to S (DNA synthesis phase) and G2 to M (mitotic phase) in the dividing cycle of malignant cells. Depriving a tumour of an essential ingredient used in phosphorylation reactions will disrupt its growth. It is also proposed that, by the same mechanism, glucagon induced hypophosphataemia renders malignant cells more sensitive to established chemotherapeutic agents and radiation waves. If this hypothesis proves to be correct, lowering intracellular phosphate may become an useful tool in cancer therapy. However extensive studies are necessary to determine whether mitosis in cancer cells can be advantageously disrupted by glucagon induced hypophosphataemia.

Topics: Acid Phosphatase; Alkaline Phosphatase; Bone and Bones; Carcinoma, Squamous Cell; Glucagon; Humans; Hydroxyproline; Hypophosphatemia, Familial; Insulin; Lung Neoplasms; Male; Mitosis; Models, Theoretical; Neoplasms; Osteitis Deformans; Phosphates; Phosphorylation; Prostatic Neoplasms

Focusing on resorption processes, we have extended our previous studies on chondroclasts and osteoclasts in normally developing tissues, using a model of nutritionally induced vitamin D-deficiency rickets. To analyze the resorption process, we investigated the matrix-resorbing cells in this modified and poorly mineralized tissue regarding morphological features and expression of tartrate-resistant acid phosphatase (TRAP) at the subcellular level. Our goal was to test the hypotheses that initiation of resorption is impaired with unmineralized matrix, and that such alterations involve changes in the subcellullar distribution of TRAP, implicating a role for this enzyme in the resorption process. Our results reveal distinctly different morphological appearances of clast-like cells in rickets compared with normal osteoclasts and chondroclasts. Ordinary resorption structures of osteoclasts and chondroclasts at the cell-matrix border, i.e., ruffled borders and clear zones, are profoundly altered in favor of a less well-defined intermediate zone. TRAP distribution at the subcellullar level is also clearly different from that in osteoclasts and chondroclasts from normal rodents, with impaired secretion; consequently, the enzyme is unable to function in the matrix outside the ruffled border. Our ultrastructural observations demonstrate that in rickets, the clasts are incapable of degrading the poorly mineralized cartilage and bone efficiently. Rachitic clasts seem to be recruited to the matrix surface and interaction between cell and matrix is also initiated, but definitive resorption structures at the cell-matrix border are not normally developed. Whether resorption is inhibited by the mere lack of mineral or mineral-associated proteins, or by other mechanisms remains to be settled.

Topics: Acid Phosphatase; Animals; Biomarkers; Bone Resorption; Hypophosphatemia, Familial; Isoenzymes; Male; Osteoclasts; Phosphates; Rats; Rats, Sprague-Dawley; Tartrate-Resistant Acid Phosphatase; Tibia

The syndrome of rickets, alopecia, hypocalcemia, and high circulating levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D) apparently is caused by resistance of target tissues to 1,25-(OH)2D. To evaluate this, we cultured cells from explants of long bone of one patient with this syndrome and from a control without any preexisting disorder of mineral metabolism. The cultured cells showed morphological features of fibroblasts but contained alkaline phosphatase activity without detectable acid phosphatase activity, indicating an osteoblastic origin for some or all of the cultured cells. Receptors for 1,25-(OH)2D were assessed by three methods: high affinity uptake of hormone in nuclei of dispersed cells, high affinity binding in hypertonic extracts (herein termed cytosol) from cells, and sedimentation velocity of bound [3H]1,25-(OH)2D3 in extracts of cell nuclei. With cells cultured from bone of the normal control, receptors for 1,25-(OH)2D exhibited properties indistinguishable from those found with cultured skin fibroblasts. With cells cultured from bone of the patient with resistance to 1,25-(OH)2D, high affinity uptake of 1,25-(OH)2D into nuclei was unmeasurable, but high affinity binding of hormone with cytosol was normal; these abnormal findings also were indistinguishable from abnormal findings obtained with fibroblasts cultured from skin of that patient.. 1) Cells cultured from explants of human bone showed morphological features of fibroblasts but retained a marker enzyme characteristic of osteoblasts. Significant admixture of osteoblast-like cells with fibroblasts was possible. 2) Cells cultured from bone of a patient with familial resistance to 1,25-(OH)2D exhibit a defect in vitamin D metabolism, indistinguishable from the defect observed with cells cultured from skin of the same patient.

Topics: Acid Phosphatase; Adolescent; Alkaline Phosphatase; Alopecia; Bone and Bones; Calcitriol; Cell Nucleus; Cells, Cultured; Child; Female; Fibroblasts; Humans; Hypocalcemia; Hypophosphatemia, Familial; Receptors, Calcitriol; Receptors, Steroid; Skin; Syndrome