Growth hormone, insulin, and insulin-like growth factor-1 in hypermobility syndrome.

OBJECTIVE: To investigate growth factors in patients with hypermobility syndrome (HMS), namely insulin, insulin-like growth factor-1 (IGF-1), and growth hormone (GH). METHODS: Standard radioimmunoassay quantified serum levels of insulin, IGF-1, and GH in 24 women and 7 men with HMS, and in suitable age and sex matched controls. Several patients with other heritable connective disorders were also studied, including congenital hip dysplasia and severe kyphosis. RESULTS: Patients with HMS and with otherwise unexplained joint and muscle pain were found to have elevated levels of insulin, IGF-1, and GH. Patients with heritable connective tissue disorders had elevated GH levels, and several patients had elevated insulin and IGF-1 levels. CONCLUSION: In patients with HMS, elevation of serum growth factors helps establish the diagnosis. GH alone can induce muscle and joint pain.

Metabolic disturbances and synovial joint responses in osteoarthritis.

Previously held views that the pathogenesis of idiopathic osteoarthritis (OA) originated in the synovial joint and was not influenced by systemic metabolic disturbances in the patient is inconsistent with recent data demonstrate skewing of the growth hormone/insulin-like growth factor-1 axis in the symptomatic OA patient. In light of this novel information, the role of growth hormone and insulin-like growth factor-1 in the pathogenesis and progression of OA requires further definition. In male patients with OA, the red blood cell sequesters more growth hormone than an aged-matched control group. Thus, this growth hormone "depot" may provide a mechanism for removal of "toxic" levels of growth hormone from the circulation. Storage of "excess" growth hormone in red cells may reduce the inflammatory or otherwise undesirable "toxic" actions of GH. In some patients, serum growth hormones levels may exceed three-times the average value considered normal. These "episodic" variations in growth hormone levels may play a significant role in the elevated levels of serum growth hormone seen in the OA patient. The connection between elevated growth hormone and decreased insulin-like growth factor-1 levels and the defined cartilage anabolic and catabolic pathways defined in in vitro assays of articular cartilage derived from the OA patients remain to be more precisely defined. However, the dampened insulin-like growth factor-1 response in OA coupled with elevated cartilage extracellular matrix degradation (mediated by metalloproteinases) and depressed compensatory biosynthesis (induced and perpetuated by the presence of cytokines such as interleukin-1 and tumor necrosis factor-alpha) may, in fact, act synergistically to suppress normal cartilage repair mechanisms thus resulting in progressive destructive lesions of the cartilage and bone.

Growth factors, insulin-like growth factor-1 and growth hormone, in synovial fluid and serum of patients with rheumatic disorders.

OBJECTIVE: Synovial fluid (SF) plays an important role in joint function. We evaluated the growth factors, insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in SF and serum from patients with osteoarthritis (OA), rheumatoid arthritis (RA), gout, pseudogout and diffuse idiopathic skeletal hyperostosis (DISH). DESIGN: Standard radioimmunoassay techniques were used to measure concurrent levels of IGF-1 and GH. SF samples and serum samples were obtained concomitantly from 27 patients with OA, 22 patients with RA, nine men with gout, 14 patients with pseudogout and eight men with DISH. RESULTS: In the case of IGF-1, a comparison of serum and SF levels shows that SF levels of IGF-1 are lower than serum levels in all groups. Men and women gave similar values. In contrast, in the case of GH, all groups, except males with RA, had higher GH values in SF when compared with serum values. Individual patients with other forms of arthritis demonstrated similar relationships. CONCLUSION: The finding that IGF-1 is present in levels about one-half as great in SF as compared with serum suggests that IGF-1 may be produced in lesser amounts or is utilized by the patient in customary joint function. The finding that GH is present in SF at values twice as high, or more, of serum levels in inflammatory arthritides suggests that GH may play a role in the pathophysiology of arthritic disorders.

Insulin levels, blood pressure and sleep apnea.

This report concerns the relative contributions of body weight and sleep apnea to the following cardiovascular risk factors: blood pressure, fasting insulin and fasting glucose. We cross-sectionally examined the relationship of various levels of apneic activity [apnea-hypopnea index (AHI)] and a measure of obesity [body mass index (BMI)] to mean morning blood pressure and fasting serum insulin and fasting blood glucose concentrations sampled the morning after polysomnography. Subjects were 261 males (age 47 +/- 13 years, mean +/- SD), who were referred to a sleep laboratory for symptoms of sleep-disordered breathing. The dependent variables, mean morning blood pressure, insulin and fasting blood glucose (FBG) levels, were significantly related to both AHI (eta'2 = 0.10) and BMI (eta'2 = 0.18). AHI and BMI combined to account for approximately 30% of the variability in the best linear combination of these three factors. Further analysis indicated that mean morning blood pressure and fasting insulin levels each correlated positively with BMI and AHI, whereas FBG correlated only with BMI. We conclude that, although these data do not prove a causal relationship, there is evidence for an independent association between sleep apnea and not only blood pressure, but also fasting insulin levels.

Growth promoting peptides in osteoarthritis and diffuse idiopathic skeletal hyperostosis--insulin, insulin-like growth factor-I, growth hormone.

OBJECTIVE: To investigate growth factors influencing bone and cartilage in patients with diffuse idiopathic skeletal hyperostosis (DISH). METHODS: Standard radioimmunoassays (INCSTAR, Stillwater, MN) quantified serum levels of insulin, insulin-like growth factor-I (IGF-I) and growth hormone (GH) in patients with DISH, in patients with osteoarthritis (OA) and in controls. Patients with DISH with comorbidity with obesity, hypertension, diabetes and coronary artery disease, also were studied. RESULTS: Patients with DISH demonstrated normal IGF-I levels; patients with OA had reduced IGF-I levels. Subjects with DISH or OA had elevated insulin and GH values. Patients with DISH with comorbidity had changes in growth factors similar to those found in patients with DISH only. There is frequent association of DISH with obesity, hypertension, coronary artery disease and diabetes mellitus suggesting that these associations are not random. CONCLUSION: Specific associations of skeletal abnormalities with clinical features in which skeletal change and clinical features combine with disturbances of insulin, IGF-I and GH exist in DISH that are distinct from OA. DISH is considered a multisystemic hormonal disorder with protean presentations.

Biochemical morbidity in sleep apnea.

The long-term goals of our research are to understand the biochemical morbidity surrounding obstructive sleep apnea syndrome to define better the need for treatment and to determine modifiable risk factors for the disease. Our current hypothesis is that sleep-related hypoxemia results in alterations in metabolic regulatory peptides, specifically insulin and insulin-like growth factors (IGF-1 and IGF-2), which are known or suspected factors for obesity and disorders such as hypertension, glucose intolerance, and atherosclerosis. Surveys of clinic populations suggest a relationship between body habitus, parameters of sleep-disordered breathing, indices of oxygenation, and insulin resistance, defined by fasting serum levels of glucose and insulin. Results will provide insight into the role of metabolic regulatory peptides in the pathogenesis of sleep-disordered breathing and the mechanisms for this association.

The role of growth factors in degenerative joint disorders.

It is postulated that osteoarthritis (OA) is associated with an imbalance between cytokine related cartilage degradation, and maintenance of proliferative and synthetic cell responses related to growth factor activity. Insulin, insulin-like growth factor (IGF-1) and growth hormone (GH) were evaluated and compared in patients with OA, and nonosteoarthritic controls. Serum levels of IGF-1 were diminished, and levels of insulin and growth hormone elevated compared to controls. In patients with diffuse idiopathic skeletal hyperostosis (DISH), serum levels of insulin and GH were elevated, but IGF-1 levels were normal. Our results suggest an interplay of growth peptides in the pathophysiology of these common disorders. The profile of growth peptide findings further distinguishes DISH from OA.

Growth promoting peptides in osteoarthritis: insulin, insulin-like growth factor-1, growth hormone.

Alterations of cartilage and bone, as seen radiographically, are fundamental features of osteoarthritis (OA). Endogenous compounds that regulate bone and cartilage metabolism were quantified by radioimmunoassay in patients with OA and in suitable normotensive controls matched for age, sex, race, height, and weight. Levels of 3 growth promoting compounds were abnormal in OA as demonstrated by low levels of insulin-like growth factor-1 (IGF-1) and elevated levels of insulin and growth hormone (GH) compared to controls. Our findings support a role for these peptides in the pathophysiology of OA.

Spondylosis in sand rats: a model of intervertebral disc degeneration and hyperostosis.

This study defines gross, histopathologic, and radiologic changes associated with intervertebral disc degeneration in a spontaneously occurring form of the disease in aging sand rats (Psammomys obesus). Sand rats (male/female) fed lab chow supplemented with desert salt bush were sacrificed at periods of 3-30 months. Lateral thoracolumbar spine films were obtained. At sacrifice, spines were surgically exposed and gross findings were recorded; after fixation/decalcification, histopathologic studies were carried out using hematoxylin and eosin, and Safranin-O with fast green counterstain. Metabolic studies included correlations of pathologic and radiologic findings with blood glucose and insulin levels. Disc-space narrowing and subchondral endplate sclerosis increased radiologically with age, with more severe lower lumbar disc lesions. Ligamentous calcifications ventral to involved discs and caudal vertebrae were common. Disc thinning and anterior vertebral bony/cartilaginous spurs were more marked with age. Microscopy revealed loss of nucleus pulposus physaliform cells, chondrocyte replication, disc necrosis, and ossification. Hyperglycemia with and without hyperinsulinemia was common. No statistically significant differences in pathologic findings were noted, neither in diabetic versus nondiabetic nor in hyperinsulinemic animals. The sand rat is a model of disc degeneration; similarities with possible overlap with diffuse idiopathic skeletal hyperostosis syndrome were noted.

Expression of insulin-like growth factor I in cultured rat hepatocytes: effects of insulin and growth hormone.

The effects of GH and insulin the accumulation of insulin-like growth factor I (IGF-I) RNA transcripts and the secretion of immunoreactive IGF-I protein were studied in rat liver hepatocytes cultured in serum-free medium. GH at concentrations of 10 ng/ml or greater stimulated the accumulation of IGF-I RNA transcripts relative to actin transcripts in poly(A)+ RNA isolated from cultured hepatocytes. The time course of IGF-I transcript accumulation in response to GH appeared to be biphasic. The transcript levels rose dramatically during the first 2 h after exposure of the cultures to GH, declined between 3 and 6 h, but reaccumulated by 24 h after exposure to GH. The presence of insulin did not influence the effect of GH on the accumulation of IGF-I RNA transcripts, although insulin did elevate IGF-I transcript levels in the absence of GH. Analysis of RNA pulse-labeled with thiouridine followed by purification of the thiol-labeled RNA using mercurated agarose indicated that GH probably acts by increasing IGF-I transcription. Insulin also affected the release of immunoreactive IGF-I into the culture medium. In the presence of insulin, immunoreactive IGF-I accumulated in the culture medium to approximately the same extent over a 24-h period regardless of whether GH was also present. In the absence of insulin, immunoreactive IGF-I accumulated in the medium only if GH was present. The results suggest that insulin may play an important role in both IGF-I transcript accumulation and the secretion of IGF-I from cultured hepatocytes.

Serum beta-endorphin in primary fibromyalgia syndrome: a controlled study.

Serum beta-endorphin was assayed without knowledge of study subject category in 44 consecutive patients with primary fibromyalgia syndrome, 3 patients with rheumatoid arthritis (RA), and 30 normal controls, all females. Mean serum beta-endorphin levels were 81 +/- 28 pg/ml in patients with fibromyalgia, whereas those in normal controls and patients with RA were 73 +/- 17 pg/mg and 73 +/- 18 pg/ml, respectively. These differences were not statistically significant. Serum beta-endorphin levels did not correlate with relevant clinical variables in either fibromyalgia or RA groups.

beta-Endorphin, immunological and biochemical changes in synovial fluid in rheumatic disorders.

In 120 patients with rheumatic disorders concomitant assays of serum and synovial fluid were done for acute phase reactants, immunoglobulins and the neuropeptide beta-endorphin. One-third of the patients with rheumatoid disease demonstrated synovial fluid levels of endorphin to be several-fold higher than serum levels, while in two-thirds the opposite results were found. These changes are discussed as adaptive or defense mechanisms. The synovial membrane is postulated to synthesize beta-endorphin.

Cryoglobulin-induced inflammation.

Inflammation of the rat footpad followed injection of cryoglobulin in crystalline form (Type I) and injection of cryoglobulin in solution (Type II). Rats deficient in essential fatty acids responded with diminished swelling which corrected to normal levels by addition of prostaglandin E1 suggesting that this reaction is prostaglandin mediated. Addition of bradykinin produced no effect. Aggregated cryoglobulin proved more inflammogenic than non-aggregated cryoglobulin. Pre-treatment with choline salicylate and colchicine reduced swelling while pre-treatment with dipyridamole increased edema following cryoglobulin inoculation. Cryoglobulin is considered to be an acute phase reactant in inflammation.

Effects of peptide hormones in urate crystal inflammation.

Effects of hormonal peptides on inflammation were investigated in normal rats receiving injections of urate crystals into the hindpaw. Beta endorphin, somatostatin and alpha melanocyte stimulating hormone injected along with urate crystals produced diminished swelling. Neurotensin and substance P produced increased swelling. Intramuscular calcitonin inhibited inflammation. In rats made deficient in essential fatty acids, thereby becoming deficient in prostaglandins, beta endorphin nullified the proinflammogenic activity of prostaglandin E2. A hypothesis is proposed that modification of inflammation by neuropeptides is part of the continuum of inflammation-regeneration, a generalized host defense mechanism against noxious stimuli.

Anti-inflammatory action of alpha-1-acid-glycoprotein in urate crystal inflammation.

Injections of alpha-1-acid-glycoprotein along with urate crystals induced less footpad swelling than that caused by injections of urate crystals alone. This anti-inflammatory action of acid-glycoprotein is considered to add further support to the hypothesis that perturbations in acute phase proteins are protective.

A new delineation of the congeries of osteoarthritis.

New concepts of osteoarthritis (OA) are reviewed as preliminary to establishing a new classification of OA, defining sub-groups of OA based on combined biochemical and clinical data. The biochemical data are derived from assays of serum proteins--transferrin, ceruloplasmin, albumin, a1-acid glycoprotein, a1-antitrypsin, immunoglobulins A, G, and M. Standard clinical techniques are followed to provide clinical data, including medical history, physical examination, x-ray studies and routine biochemical tests. Genetic polymorphism is proposed as an explanation for subsets of OA. Extensive family history data is important in establishing connections.

Age related changes in total DNA and RNA and incorporation of uridine and thymidine in rat brain.

1. Total brain DNA and total brain RNA and the incorporation of thymidine[14C] and uridine[3H] were measured in young and aged rats. 2. From 20 days to the time of sexual maturation, both DNA and RNA levels increase. Total RNA exceeds total DNA at all ages. Comparatively, the ratio of total DNA/RNA is higher in young than in aged animals. 3. The incorporation of thymidine[14C]/g of DNA and of uridine[3H]/g of RNA decreases with age. This decrease is rapid in young animals. After 350 days of age, the incorporation becomes very low. The significance of data is discussed.

Age-related changes in total DNA and RNA and incorporation of uridine and thymidine in rat liver, kidney and spleen.

Total content of DNA and RNA in liver, kidney and spleen were measured in young and aged rats. At the same time the incorporation of [14C]thymidine, a DNA precursor, and [3H]uridine, an RNA precursor, were also determined. Changes in total organ DNA and RNA correlated with sexual maturation as did incorporation of precursors. Young animals have more DNA per organ relative to RNA, with kidney and spleen DNA showing a decrease between maturity and senescence. However, liver RNA increases with age, a change probably due to decreased catabolism of RNA since [3H]urine uptake decreases. Liver polyploid differentiation, and [14C]thymidine and [3H]uridine uptake, are correlated. In kidney, incorporation of [3H]uridine is inversely related to [14C]thymidine incorporation.