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.

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.

Lysyl oxidase and Maillard reaction-mediated crosslinks in aging and osteoarthritic rabbit cartilage.

Alterations in the integrity of the extracellular matrix play an important role in osteoarthritis. Matrix crosslinks in articular cartilage of the knee were studied in partially meniscectomized rabbits to compare changes due to osteoarthritis with those occurring during aging. Pyridinoline, a lysyl oxidase-initiated crosslink, and pentosidine, a crosslink formed by the Maillard/glycation reaction, were assayed separately on reverse-phase high performance liquid chromatography. A significant increase in the percentage of insoluble collagen was observed in normal 12-month-old rabbits compared with the levels in 3-month-old animals, whereas osteoarthritis was associated with a shift toward more soluble fractions. Total pyridinoline content did not change with age or osteoarthritis. Total pentosidine, however, increased significantly with age but remained constant with osteoarthritis. Analysis of the distribution of crosslinks among solubility fractions indicated a significant shift of pyridinoline from the pepsin-released fraction to the insoluble fraction with osteoarthritis, but no changes were observed with age. Pentosidine distribution shifted toward the pepsin-released fraction in osteoarthritis, with a shift toward the insoluble fraction with age. Because of the low levels of pentosidine present, its precise location, whether collagenous or noncollagenous, remains unclear. However, since pentosidine represents a marker for the overall Maillard reaction, the results of our studies support a role for Maillard reaction products in the aging of extracellular matrix. The shift of pentosidine toward more soluble fractions suggests the presence of matrix degradation and repair in osteoarthritis.

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.

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.

IgG-induced experimental immune synovitis: hormonal modulation of in vitro splenic immune responses to homologous antigens.

The effect of oestrogen or anti-oestrogen administration on gross pathology and in vitro cell-mediated immune responses to homologous IgG, native and denatured interstitial collagens and PPD was studied in an IgG-induced rabbit model of immune synovitis. During induction of synovitis, rabbits were administered oestradiol valerate (0.075 mg/kg/day) or tamoxifen, an anti-oestrogen (2.0 mg/kg/day, high dose or 0.5 mg/kg/day, low dose) or placebo injections. Low dose tamoxifen administration was associated with significant improvement P less than 0.05 in immune synovitis with regard to gross pathology, when compared to placebo and the oestradiol treatment group. High dose tamoxifen treatment was not associated with significant improvement in observed synovitis. With regard to cell-mediated immune responses, spleen cells derived from immune synovitis rabbits were observed to increase 3H-thymidine uptake on incubation with native or denatured homologous collagens. Modulation of these immune responses to antigens was observed in anti-oestrogen treated rabbits with immune synovitis. In vitro cell-mediated immune responses to denatured type I, II and III collagens, PPD, as well as native type II and III collagens were not observed in the low dose tamoxifen treatment group. However, in vitro immune responses to these antigens were observed in spleen cell cultures from immune synovitis rabbits treated with either high dose tamoxifen or oestradiol valerate. The data suggest that in vivo anti-oestrogen administration can modulate the in vitro cell-mediated immune response to connective tissue constituents observed in immune synovitis. Concomitant with reduced immune responses is a significant reduction in the observed lesions of the inflammatory response.

Estradiol and tamoxifen stimulation of lapine articular chondrocyte prostaglandin synthesis.

The effect of estradiol and tamoxifen on prostaglandin (PG) synthesis by rabbit articular chondrocytes in secondary monolayer cultures was investigated. Radioimmunoassay for PGE2, PGF2 alpha, 6-oxo-PGF1 alpha and thromboxane B2 was performed on media from cultures containing estradiol and tamoxifen (10-12M-10-7M). Radiometric thin-layer chromatography was also carried out. The time course of estradiol/tamoxifen effect on chondrocyte PG synthesis was evaluated and its relationship to cell density in culture examined. Estradiol stimulated the synthesis of PGs by chondrocytes. Stimulation was noted at picomolar concentrations of estradiol without further stimulation at markedly higher concentrations. In time studies, after a lag, the effect of estradiol was present fully by 5 hrs, remained steady for 24 hrs and then declined by 48 hrs. Estradiol stimulation of PG synthesis was dependent upon chondrocyte culture plating density. Tamoxifen stimulated chondrocyte PG synthesis to relatively lower levels than estradiol. The characteristics of estradiol/tamoxifen stimulation of chondrocyte PG synthesis suggest a mechanism involving estradiol cytoplasmic receptors.

Intraarticular hyaluronic acid injection and synovial prostaglandins in experimental immune synovitis.

In vitro studies suggest that synovial fluid hyaluronic acid may have a role in reducing joint inflammation. The effect of intraarticular injection of sodium hyaluronate in a model of experimental immune synovitis was assessed. In addition, tissue prostaglandin content of synovia with and without immune synovitis was compared. Intraarticular hyaluronic acid administered at 2 doses was not effective in reducing the induced inflammation. With immune synovitis there was an increase in the total synovial prostaglandins. When related to total prostaglandins, prostacyclin was decreased, prostaglandin F2 alpha and thromboxane were increased and prostaglandin E2 was the same in synovitis as compared to controls.