Louis Lippiello

The Association of Lipid Abnormalities With Tissue Pathology in Human Osteoarthritic Articular Cartilage

Articular cartilage is one of very few body tissues uniquely characterized as having substantial stores of lipid deposits. Lipid droplets are naturally accumulated by chondrocytes and individual fatty acids have been shown to have protective as well as deleterious effects on cartilage degradation in animal models of degenerative joint disease. As a means to better assess the role of lipids in human joint pathology, a comparative analysis of fatty acids was undertaken in small segments of osteoarthritic articular cartilage. The data were assessed in terms of chondrocyte synthetic activity and histological determination of disease severity. The distribution profile of individual fatty acids in normal and osteoarthritic specimens remained constant, with palmitic, oleic, and linoleic acids representing 85% of the total fatty acids. In contrast, levels of total fatty acids were markedly increased in association with increasing degree of lesion severity. Compared with tissue from normal-aged joints, grade 0 to 1 mild lesions had elevated levels of total fatty acids, essential fatty acids, and chondrocyte synthetic activity of 80%, 312%, and 393%, respectively. More severe tissue involvement (grade 6 to 9), was associated with even greater increases of 440%, 1,100%, and 1,150%, respectively. No change was noted in cholesterol content in any tissue. The accumulation of arachidonic acid was greater than the proportional increase in total fatty acid content and was primarily distributed into the neutral lipid fraction, where it constituted almost 62% of the fatty acid level in tissues of moderate lesion severity. There was an association of lipid accumulation in general and arachidonic acid in particular with histological severity.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative Roentgenographic Densitometry for Assessing Fracture Healing

A noninvasive method was developed to assess fracture healing using optical densitometric methodology. Photometric measurements of osseous tissue density were based on illuminance or intensity of light, transmitted through standard roentgenograms. The method was tested in 6-mm tibial segmental defects and single-cut osteotomy defects in adult mongrel dogs. The lowest measureable bone density in the defect was compared to bending rigidity of the involved extremity. For both types of defect, an exponential relationship was found between the densitometric evaluation of the healing fracture gap and bending rigidity. This method proved superior to a roentgenographic scoring method and is capable of detecting small differences in mineral content using standard roentgenograms. The high correlation between densitometric evaluation and bone rigidity indicates this method has potential for use in the in vivo assessment of fracture healing.

Lipid and Cell Metabolic Changes Associated with Essential Fatty Acid Enrichment of Articular Chondrocytes

Abstract Observations of impaired chondrocyte metabolism in essential fatty acid (EFA) deficiency as well as EFA protection against development of osteoarthrosis in inbred mice suggest the existence of a relationship between EFA, chondrocyte metabolism, and cartilage degeneration. To explore this relationship further, the fatty acid content of lipids in normal fetal bovine chondrocytes was manipulated by in vitro exposure to media supplemented with 100 μM arachidonic acid (20:4) or oleic acid (18:1). Chondrocytes rapidly and differentially incorporated both fatty acids into their lipid pools. The predominant acceptor was triacylglycerols. A 980% enrichment of arachidonic acid was associated with increased concentrations of fatty acids, increased 35SO4 and [3H]proline incorporation into matrix macromolecules (170% and 54–103%, respectively), and a 24-fold elevation in chondrocyte prostaglandin synthesis. No metabolic changes were observed in cells enriched by 377% with 18:1 oleic acid. The metabolic effects elicited by 20:4 arachidonic acid were abolished by pretreatment of cells with indomethacin, suggesting that the cellular responses to essential fatty acid loading may be associated with induced increases in prostaglandin synthesis. The data indicate that excessive in vitro accumulation of arachidonic acid is associated with an increase in synthetic activity that is causally related to increased prostaglandin synthesis and elevated levels of cellular fatty acids.

Is Glutamate-Induced Reduction in Growth Hormone-Releasing Hormone a Neuroendocrine Model of Aging in the Rat?

Abstract Decreases in serum growth hormone (GH) associated with aging may be a result of age-related degenerative changes in neurons of the hypothalamus resulting in a decrease of growth hormone-releasing hormone (GHRH). This study tests the utility of glutamate-induced hypothalamic neuronal degeneration in the rat as a neuroendocrine model of aging. Sprague-Dawley female rats received three 4-mg/g monosodium glutamate (MSG) subcutaneous injections during the first 5 days following birth. Animals were anesthetized at 60 days of age and challenged with GHRH. Blood samples were assayed for GH. Serum GH levels following GHRH challenge in the MSG-treated group rose more slowly and to a lower peak than in controls (P < 0.05). There was no difference in total GH release over the 1-hr interval following challenge. MSG-treatment of animals resulted in lower gross body (P < 0.05) and kidney (P < 0.05) weights with no difference in ovary or adrenal weights. There were also no differences In pituitary GH or total protein content between the groups. Analysis of femurs in the MSG animals revealed both a lower bone strength (P < 0.05) and maximum mid-shaft diameter (P < 0.05), but no difference in length, mineral/matrix ratio, or tissue density. Our data suggest that the degree of neuroendocrine disruption resulting from neonatal MSG administration mimics in part systemic changes commonly observed in aged animals. Hence, definite similarities exist between MSG treatment and the documented aging-related changes in hypothalamic GHRH content and GH regulation in the rat.

Uncertain effect of indomethacin on physeal growth injury: experiments in rabbits

Growth arrest and shortening remain significant sequelae of growth-plate injuries. Nonsteroidal anti-inflammatory agents, known to inhibit callus and bone formation, may be useful to diminish callus-induced growth effects after epiphyseal fracture. In this study, we created a longitudinal osteotomy of the medial distal femoral condyle in 54 rabbits to model a Type IV epiphyseal fracture. We treated half with indomethacin and half with normal saline for 6 weeks. Nineteen animals of each group developed deformity, with indomethacin-treated animals averaging only slightly less angulation than the controls. However, the mean femoral shortening was less in the indomethacin-treated animals as compared with the controls.

Prostaglandins and articular cartilage metabolism: Does prostaglandin perturbation perpetuate cartilage destruction?

Abstract There is sufficient evidence available attesting to the in vitro inhibitory effect that PGs have on articular cartilage metabolism. In view of the indomethacm sensitivity of substances secreted by RS in culture, the elevated levels of PGs found in synovial fluid from rheumatic joints, and the suggestion of the presence of an inflammatory aspect in osteoarthritis, it is becoming suspect that similar circumstances may exist in vivo. That inhibition of proteoglycan synthesis by PGs may play a role in development and/or progression of cartilage changes is compatible with (1) in vitro evidence of a positive feedback system of PC synthesis (hence the vicious cycle terminology) and (2) the essential irreversability of the PG inhibitory effect. However, this inhibition of cartilage metabolism is most readily seen at what must be considered pharmacologic doses. How can we reconcile these effects when levels of endogenous PG are several orders of magnitude less, even in inflammatory disease? Moreover, it is becoming disturbingly clear that various PGs may have opposing metabolic effects (i.e., PGI stimulation of metabolism) so that the overall role of PGs in cellular regulation may be dependent upon the algebraic sum of the various subtypes. These questions must still be addressed, but it is certainly a tenable concept that homeostatic regulation and responsiveness of cartilage to external stimuli (in the absence of neural and vascular elements) may indeed be mediated by PG modulation of metabolism.