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Biomedical subjects

A M Parfitt

Publications and source records attributed to A M Parfitt.

At least 73 records · Page 4Linked to original sources
PubMed1996

Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia.

BACKGROUND: An activating mutation of the receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) was recently found in a patient with Jansens's metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism associated with hypercalcemia and normal or low serum concentrations of the two hormones. To investigate this and other activating mutations and to refine the classification of this unusual disorder, we analyzed genomic DNA from six additional patients with Jansen's disease. METHODS: Exons encoding the PTH-PTHrP receptor were amplified by the polymerase chain reaction (PCR), and the products were analyzed by gel electrophoresis or direct nucleotide-sequence analysis. Nucleotide changes were confirmed by restriction-enzyme digestion of genomic DNA or the PCR products. RESULTS: The previously reported mutation, which changes a histidine at position 223 to arginine (H223R), was found in genomic DNA from three of the six patients but not in DNA from their healthy relatives or 45 unrelated normal subjects. A novel missense mutation that changes a threonine in the receptor's sixth membrane-spanning region to proline (T410P) was identified in another patient but not in 62 normal subjects. In two patients with radiologic evidence of Jansen's metaphyseal chondrodysplasia but less severe hypercalcemia, no receptor mutations were detected. In COS-7 cels expressing PTH-PTHrP receptors with the T410P or H223R mutation, basal cyclic AMP accumulation was four to six times higher than in cells expressing wild-type receptors. CONCLUSIONS: The expression of constitutively active PTH-PTHrp receptors in kidney, bone, and growth-plate chondrocytes provides a plausible genetic explanation for mineral-ion abnormalities and metaphyseal changes in patients with Jansen's disease.

Base Sequence↗
PubMed1996

Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence.

Bone marrow is the principal site for osteoclastogenesis and osteoblastogenesis; and an increase in the former has been linked with bone loss caused by acute loss of gonadal steroids. We have now used an established murine model of accelerated senescence and osteopenia (SAMP6) to test the hypothesis that reduced osteoblastogenesis is linked with decreased bone mass. At 1 mo of age, the number of osteoblast progenitors in SAMP6 marrow was indistinguishable from controls; however a threefold decrease was found at 3-4 mo of age. Impaired osteoblast formation was temporally associated with decreased bone formation and decreased bone mineral density, as determined by histomorphometric analysis of tetracycline-labeled cancellous bone and dual-energy x-ray absorptiometry, respectively. Osteoclastogenesis determined in ex vivo bone marrow cultures was also decreased in these mice, as was the number of osteoclasts in histologic sections. Moreover, unlike controls, senescence-accelerated mice failed to increase osteoclast development after gonadectomy. The osteoclastogenesis defeat was secondary to impaired osteoblast formation as evidenced by the fact that osteoclastogenesis could be restored by addition of osteoblastic cells from normal mice. These findings provide the first demonstration of a link between low bone mineral density and decreased osteoblastogenesis in the bone marrow and validate the senescence-accelerated mouse as a model of involutional osteopenia.

Aging↗
PubMed1996

Effect of ethnicity and age or menopause on the structure and geometry of iliac bone.

We measured indices of bone volume (cancellous, cortical) and bone surface (cancellous, endocortical, and intracortical) in intact full-thickness transiliac bone biopsies obtained from 144 healthy women aged 20-74 (35 black and 109 white, 62 premenopausal and 82 postmenopausal). The data were analyzed by two-way analysis of variance of the four groups defined by age/menopause and ethnicity and by linear regression of major variables on age. None of the interaction terms was significant, and none of the regression slopes on age differed between blacks and whites, indicating that the effects of ethnicity and of age/menopause were independent. Accordingly, the data were also analyzed separately for the effects of ethnicity (pre- and postmenopausal combined) and age/menopause (blacks and whites combined). The analyses led to the following conclusions. (1) Blacks have more cancellous and cortical bone than whites in the ilium; the difference was due to thicker trabeculae and thicker cortices with no difference in trabecular number or cortical porosity. (2) The magnitude of the black/white differences was the same throughout the age range covered by the study, indicating differences in peak adult values, not in rates of loss with age. (3) As the result of age/menopause, there were significant reductions in all indices of the amount and structure of bone except for trabecular thickness; the magnitude of the reductions was the same in blacks and whites. (4) Cancellous bone loss was mainly the result of the complete removal of some trabecular elements with increased separation between remaining elements. Cortical bone loss was due to thinning from the endocortical surface with a small but significant contribution from increased cortical porosity, due to an increased number of intracortical canals. These patterns of bone loss were the same in blacks and whites. (5) Although the percentage losses of bone with age/menopause were higher for cancellous than for cortical bone, the absolute amounts of bone lost were about the same for cortical as for cancellous bone. (6) The ratio of surface to tissue volume decreased with age/menopause in cancellous bone but increased in cortical bone; rates of bone loss would change in the same manner if the loss per unit of surface remained constant. (7) The total extent of bone surface in the ilium did not change with age/menopause, so that the surface/volume ratio for the entire bone increased; volumetric bone turnover would increase and bone age decrease if remodeling activity per unit of surface remained constant.

Adult↗
PubMed1996

Phosphate administration increases both size and number of parathyroid cells in adult rats.

Phosphate administration increases both parathyroid hormone (PTH) secretion and parathyroid size in rats, but the relative contribution of hypertrophy and hyperplasia is unknown. Accordingly, we reexamined parathyroid histology in a previously published experiment [6], quantitatively rather than qualitatively. Ninety female Long-Evans rats were divided into six groups; three were given a normal diet, and three a high phosphate diet (Ca/P 1:7). One group from each arm was killed after 1, 2, and 3 months. Quantitative microscopy was performed on the parathyroid section with the largest area from each animal, without knowledge of its experimental status. Total gland area and total number of cell profiles did not change significantly in the control rats, but increased progressively in the phosphate-loaded rats. At 3 months, the difference was +194% for gland area and+151% for profile number (P < 0.0001), much more than could be accounted for by suppression of apoptosis. Mean nuclear profile area and mean cell profile area (including associated connective tissue as well as cytoplasm) were both significantly increased at 1 month (P < 0.0001). The differences persisted, but their magnitudes (about +16%) did not change further. This time course was consistent with the morphologic expression of increased PTH secretory activity. We conclude that phosphate administration to adult rats increases both size and number of parathyroid cells, the latter due to increased cell proliferation. Phosphate-stimulated parathyroid growth could be due to either hypocalcemia or decreased calcitriol production; increased cell division may also be linked to increased hormone secretion, regardless of its cause. The relative importance of these different mechanisms remains to be determined.

Animals↗
PubMed1996

Parathyroid cell proliferation in the rat: effect of age and of phosphate administration and recovery.

Indirect evidence in human subjects and the low prevalence of mitotic figures in rats suggest that the adult parathyroid gland is a conditional renewal tissue with a low cell birth rate and long cell life span. Accordingly, in normal rats of different ages (8-22 weeks), we measured parathyroid cell and nuclear size, cell number, and gland volume by quantitative microscopy, and cell birth rate and cell life span by Ki-67 expression assuming a duration of expression of 24 h. We also examined the effects of phosphate administration and subsequent recovery. In normal rats, parathyroid volume, cell and nuclear profile area, and cell profile number did not change significantly between 8-22 weeks of age. In younger rats, the calculated cell birth rate was 53.2%/yr, and mean cell life span was 1.9 yr, with a lower 95% confidence limit based on a logarithmic distribution of 6 months. Phosphate loading caused hyperphosphatemia, hypocalcemia, increased PTH secretion, and increased calcitriol production. There was an increase in parathyroid cell and nuclear size consistent with PTH hypersecretion per cell, but a larger increase in cell number and gland volume due to a 3-fold increase in cell birth rate. Six weeks after withdrawal of phosphate administration, cell and nuclear size had fallen to normal, and cell birth rate to half-normal, but cell number and gland volume were even higher. No apoptosis was detected in any gland in any animal, probably because it is short and infrequent, rather than absent altogether. The following conclusions were made. 1) In normal rats, parathyroid cell birth rate is very low, but can be increased by hypocalcemia, establishing the status of the parathyroid gland as a conditional renewal tissue. 2) Despite subnormal cell birth rate, the hyperplasia induced by 8 weeks of phosphate administration could not regress to normal within the animal's remaining life span.

Aging↗
PubMed1996

Hypercalcemia due to constitutive activity of the parathyroid hormone (PTH)/PTH-related peptide receptor: comparison with primary hyperparathyroidism.

In Jansen's disease (JD), the hypercalcemia found in about half the cases is the result of a mutant, constitutively overactive, form of the PTH/PTHrP receptor, which in these cases also causes the skeletal dysplasia. The subject of the present report was first seen in 1956 and is still under treatment at the same medical center. We report the clinical course and a detailed study of calcium and bone metabolism carried out in 1976 and compare the results with those of six typical patients with mild primary hyperparathyroidism in whom exactly the same studies were carried out. In the patient with JD, the hypercalcemia was of early onset; chronic and nonprogressive; refractory to the administration of phosphate, glucocorticoid, and calcitonin; and accompanied by suppressed PTH levels as determined by two different immunoassays, an undetectable PTHrP level, increased excretion of nephrogenous cAMP (an in vivo bioassay of endogenous PTH production), decreased tubular reabsorption of phosphate, increased tubular reabsorption of calcium, increased biochemical indexes of bone turnover, and increased histological indexes of bone turnover on iliac bone histomorphometry after double tetracycline labeling. There was exaggerated loss of cortical bone and preservation of cancellous bone. All the results in JD relating to renal or skeletal effects of PTH excess were within or close to the ranges found in the hyperparathyroid patients, except that tubular reabsorption of phosphate was more depressed. Because PTH secretion was suppressed, any effects mediated by putative alternative receptors would have been diminished. We conclude that 1) the hypercalcemia due to constitutive overactivity of the PTH/PTHrP receptor is indistinguishable from that of mild primary hyperparathyroidism in clinical characteristics and renal tubular and skeletal features; and 2) the classic laboratory manifestations of primary hyperparathyroidism, with the possible exception of osteitis fibrosa cystica, can all be accounted for by overactivity of a single receptor.

Bone Diseases, Developmental↗
PubMed1995

Relations between histologic indices of bone formation: implications for the pathogenesis of spinal osteoporosis.

Wall thickness, a major determinant of trabecular thickness, falls with age and falls further in osteoporosis. To estimate the importance of defective osteoblast recruitment in the pathogenesis of this defect, we compared various histologic indices of bone formation in iliac bone biopsies in three groups of subjects--healthy premenopausal women, healthy postmenopausal women, and patients with postmenopausal osteoporosis and at least one non-traumatic vertebral compression fracture. Indices that reflect the frequency of activation of bone remodeling and consequent birth rate of new teams of osteoblasts (osteoid surface, mineralizing surface, osteoblast surface, and bone formation rate, all expressed per unit of bone surface) were each higher in healthy subjects who were postmenopausal than in those who were premenopausal, but lower in osteoporotic than in normal postmenopausal women. In each group, the primary surface measurements were significantly correlated with each other, but the correlation was less close in those with osteoporosis. Indices that reflect the average collective performance of individual teams of osteoblasts (mineralizing surface and osteoblast surface per unit of osteoid surface, mineral apposition rate, adjusted apposition rate, and wall thickness) were all lower in postmenopausal than in premenopausal normal subjects, and even lower in those with postmenopausal osteoporosis. The parameters of the regression lines relating bone formation rate to osteoblast surface were essentially the same in each group, indicating that bone formation rate per unit of osteoblast surface was unaffected by age or menopause, and was the same in osteoporosis as in healthy subjects of similar age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Ethnic differences in regional bone density, hip axis length, and lifestyle variables among healthy black and white men.

There are few published data on bone mass, measured by dual-energy X-ray absorptiometry (DXA), in healthy white or black men. Similarly, a recently described predictor of hip fracture among white women, hip axis length (HAL), has not been studied in men. We recruited 160 white and 34 black men, aged 23-80 years, and screened for diseases and drug exposures that adversely affect skeletal health. We measured bone mineral density (BMD) in the lumbar spine, femoral neck, and radial shaft by DXA; height and weight; skin color by reflectometry; and hip axis length both directly from DXA output and using automated software in a subsample. We also obtained historical data on education, smoking, exercise, and fractures. There were no significant black/white differences in mean weight, height, body mass index (BMI), or HAL. The black men had higher BMDs than did the white men at every site (5% for the radius, 10% for the lumbar spine, and 20% for the femoral neck). Skin pigmentation and BMD were not significantly correlated in either group (p > 0.38). Among the white men, smoking was associated with lower lumbar BMD, but there was no significant relationship between BMD and exercise frequency in either group. There was no significant ethnic difference in fracture experience. We conclude that: (1) the higher BMD in black men than in white men is not due to greater body size, (2) the lower hip fracture risk reported for black men than for white men is not due to a difference in hip axis length; (3) skin color is not related to BMD in either sex.

Absorptiometry, Photon↗
PubMed1995

Bone loss and bone turnover in diabetes.

There have been conflicting reports about the effect of diabetes on bone density. In 1978, we studied 109 patients, 46 with type I and 63 with type II diabetes; approximately 12 years later we restudied 35 of the 66 surviving patients. In the original study, radial bone density did not differ significantly between patients with either type of diabetes but was significantly lower than in nondiabetic control subjects. In eight osteopenic patients, bone formation rate and other histological indexes of osteoblast recruitment and function were markedly depressed compared with those in nondiabetic control subjects. In patients remeasured approximately 2.5 years (41 patients) and approximately 12.5 years (35 patients) after baseline, bone loss had continued at the expected rate in patients with type I diabetes, with maintenance of the same deficit, but was slower than expected in patients with type II diabetes, such that the initial deficit had been completely corrected. In six of the eight patients who had undergone bone biopsy, one with type I and five with type II diabetes, the mean bone mineral density z-score of the spine and femoral neck approximately 12 years later was > 0 and in one subject was significantly higher than normal at both sites. Based on these data and on previous studies, we propose that in patients with diabetes, low bone formation retards bone accumulation during growth, metabolic effects of poor glycemic control lead to increased bone resorption and bone loss in young adults, and low bone turnover retards age-related bone loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Bone remodeling, normal and abnormal: a biological basis for the understanding of cancer-related bone disease and its treatment.

Remodeling the cyclical replacement of old bone by new, serves to maintain its mechanical and metabolic functions. In each cycle a circumscribed volume of bone is removed by osteoclastic resorption and subsequently replaced by osteoblastic formation at the same location. Remodeling is carried out by elongated structures known as basic multicellular units (BMU) that travel through or across the surface of bone. Each BMU lasts about six months, with continued sequential recruitment of new osteoclasts and osteoblasts. Abnormal bone remodeling involves some combination of loss of directional control, increase in number of remodeling cycles and incomplete replacement. In metastatic bone disease, tumor cells find the hematopoietic bone marrow conducive to their survival and growth, because they can manipulate the local cytokine network to increase recruitment of osteoclasts from local precursors and so increase bone resorption. The effect on bone formation is biphasic; an initial increase is due partly to the normal evolution of the BMU, and partly to the induction of reparative woven bone formation. Later, normal BMU-based bone formation may fall to subnormal levels. In some tumors, a generalized increase in osteoclast recruitment and decline in bone formation are the systemic responses to one or more agents released by tumor cells into the circulation, of which the most frequent is parathyroid hormone-related peptide, but in both metastatic and non-metastatic disease, the cellular events in bone are essentially the same. Cancer-related bone disease is amenable to treatment with drugs that inhibit osteoclast recruitment, of which the bisphosphonates are the most effective. Treatment should be started before there has been irreparable damage to bone structure and before the onset of hypercalcemia. Although bisphosphonates remain in bone for a long time, adverse effects are very unlikely within the patient's lifetime.

Biology↗
PubMed1994

Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone.

The bone replacement process in the adult skeleton is known as remodeling. When bone is removed by osteoclasts, new bone is laid down by osteoblasts in the same place, because the load bearing requirement is unchanged. Bone is usually replaced because it is too old to carry out its function, which is mainly mechanical in cortical bone and mainly support for homeostasis and hematopoiesis in cancellous bone. Remodeling always begins on a quiescent bone surface, separated from the marrow by flat lining cells that are one of the two modes of terminal differentiation of osteoblasts. Lining cells are gatekeepers, able to be informed of the need for remodeling, and to either execute or mediate all four components of its activation-selection and preparation of the site, recruitment of mononuclear preosteoclasts, budding of new capillaries, and attraction of preosteoclasts to the chosen site where they fuse into multinucleated osteoclasts. In cortical bone, osteonal remodeling is carried out by a complex and unique structure, the basic multicellular unit (BMU) that comprises a cutting cone of osteoclasts in front, a closing cone lined by osteoblasts following behind, and connective tissue, blood vessels and nerves filling the cavity. The BMU maintains its size, shape and internal organization for many months as it travels through bone in a controlled direction. Individual osteoclast nuclei are short-lived, turning over about 8% per d, replaced by new preosteoclasts that originated in the bone marrow and travel in the circulation to the site of resorption. Refilling of bone at each successive cross-sectional location is accomplished by a team of osteoblasts, probably originating from precursors within the local connective tissue, all assembled within a narrow window of time, at the right location, and in the right orientation to the surface. Each osteoblast team forms bone most rapidly at its onset and slows down progressively. Some of the osteoblasts are buried as osteocytes, some die, and the remainder gradually assume the shape of lining cells. Cancellous bone is more accessible to study than cortical bone, but is geometrically complex. Although remodeling conforms to the same sequence of surface activation, resorption and formation, its three-dimensional organization is difficult to visualize from two-dimensional histologic sections.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

The two faces of growth: benefits and risks to bone integrity.

Bones grow by two processes: cortical bone is made by periosteal apposition (growth in width), and cancellous bone is made by endochondral ossification (growth in length). In both the axial and appendicular skeleton, about half of peak adult bone mass is accumulated during the adolescent growth spurt, which occurs two years earlier in girls than in boys, and is under pituitary control via interactions between growth hormone and sex hormones. Throughout growth, but particularly during adolescence, the ability of bone to adapt to mechanical loading is much greater than after maturity. This is the main reason why the effects of physical activity on bone are greater in cross-sectional studies in young athletes than in longitudinal studies in previously sedentary adults. In wild animals, by the time growth has ceased, the bones must be as strong as they will ever need to be, and attainment of further strength after cessation of growth would serve no biologic purpose. Adaptation of growing bone to mechanical loading is the purpose of the mechanostat, which enables physiologic adaptation in individuals to establish and maintain a species-specific property of the bones that is determined by evolutionary adaptation in populations. But growth confers risks as well as benefits to the skeleton. The large increase in incidence of upper extremity (particularly lower forearm) fractures, coincident with the adolescent growth spurt in both sexes, is due to an increase in cortical porosity as a consequence of an increase in intracortical bone turnover, which supplies some of the calcium needed by the growing ends of the long bones. This enables an increased demand for calcium to be spread over a longer time, analogous to the cyclic physiologic osteoporosis which occurs during the antler growth cycle in deer. The subsequent decline in cortical porosity is responsible for the continued increase in radial bone density after cessation of growth, referred to as consolidation. In the present state of knowledge, an increased incidence of fracture during the adolescent growth spurt is the inescapable consequence of an appropriate level of physical activity, and is the price that has to be paid in order to maximize bone accumulation during growth and minimize fracture risk in old age.

Adolescent↗