The Potential Role of Prostaglandins in Skeletal and Muscular Disorders *

ROBERT B. ZURIER, M.D.

Division of Rheumatic Diseases, Department of Medicine, University of Connecticut School of Medicine Farmington, CT 06032

ABSTRACT Musculoskeletal diseases such as rheumatoid arthritis and polymyositis are characterized by chronic inflammation. There is evidence to suggest that prosta glandins participate in the production of the inflammatory response. In several tissues, the production of inflammation has been associated with the release of prostaglandins. The inhibitory effect of some anti-inflammatory agents on prosta glandin synthesis further suggests a prostaglandin role in inflammation. Reduction by prostaglandins of release from cells of mediators of inflammation has been described. Prostaglandin treatment also suppresses acute and chronic inflam mation in several experimental models. Thus, prostaglandins may serve to regu late the inflammatory response.

Introduction substances in crystalline form and described their chemical structure.3 The first clue to the existence of prosta glandins emerged in 1930 when two New York City gynecologists observed that Structure human myometrium exhibited rhythmic The basic structure common to all prosta contractions and relaxation when incubated glandins is a prostanoic acid skeleton, a 20 with fresh human semen.19 Goldblatt10 and carbon atom unsaturated hydroxy fatty acid von Euler33 independently confirmed this with a cyclopentane ring at C8-C 12 (figure finding and identified the active principle as 1). In nature, the prostaglandins are an acidic lipid which von Euler believed to produced from the corresponding polyun be produced in the prostate gland and saturated fatty acid by a microsomal therefore named prostaglandin. Eliasson8 synthetase system. They are unusual among later demonstrated that prostaglandin in highly active biological compounds in that human semen is, in fact, derived from they lack nitrogen, in which respect they re seminal vesicles. Bergstrom and Sjovall2 semble the steroid hormones. The prosta found the active substance to be not one but glandins are grouped according to the type several closely related compounds. Using of chemical functionality present. Thus, homogenates of sheep vesicular glands, prostaglandins are divided into the E, F, A these investigators isolated two of the and B compounds by the nature of the five "Supported by NIH Grant #1R01-AM-17309-01 and membered ring functions (figure 2). The two Arthritis Foundation Clinic Center Grant. main series, prostaglandins E and F (PGE,

276 PROSTAGLANDINS IN SKELETAL AND MUSCULAR DISORDERS 277

for synthesizing prostaglandins from essential fatty acids. It therefore seems un likely that the prostaglandins are part of a classical endocrine-target organ system. PROSTANOIC ACID They may, however, serve as local regulators Figure 1. Prostanoic acid. The basic structure of a of cell functions. The prostaglandins possess fully saturated C20 acid with C8 to C12 closed to form a 5-membered ring is designated prostanoic acid. a broad spectrum of pharmacological activities34 which, in several cases, appear to PGF) differ only in the presence of a ketone involve changes in cyclic adenosine 3',5'- or hydroxyl function at C9. The subscript monophosphate (cAMP) concentrations. numeral after the letter indicates the degree The first of these changes to have been of unsaturation in the alkyl and carboxylic measured was in adipose tissue,4 where prostaglandins were found to decrease side chains. Thus, whereas the numeral 1 in cAMP levels in isolated fat cells. A more dicates the presence of a double bond at £13-14 (pQEJ, the numeral 2 marks the usual effect of prostaglandins is to increase levels of cAMP14 by virtue of activating presence of an additional double bond at membrane adenyl cyclase in a manner com C5-6 (PGE2) and the numeral 3 denotes a mon to the action of many hormones. third double bond at C 17-18 (PGE3). Sub stituents on the same side of the ring as the carboxyl group are in the alpha position and Relation to Inflammation those on the same side as the alkyl group are Stimulation of cells and tissues, whether in the beta position. That is, below the plane by mechanical, hormonal or neurologic of the ring is designated alpha and above is means, results in the increased biosynthesis designated beta. In the presence of weak of prostaglandins.25 It has been suggested acid or alkali, the PGE compounds undergo that one such stimulus is inflammation, in dehydration within the ring resulting in the course of which phospholipases are freed formation of the PGA compounds. In the from the lysosomes of phagocytes, cells presence of stronger alkali the C 10-11 double which often become the center of inflamma bond rearranges to the 8, 12 position, and tory lesions.22 For example, it has been PGB compounds are formed (figure 2). Thus, demonstrated in patients with rheumatoid the six naturally occurring PGE and PGF arthritis that synovial fluid leucocytes and compounds are designated as primary com synovial lining cells contain intracytoplas- pounds since none is a precursor of any other mic particulate complexes consisting of im in this group. munoglobulins and complement compo nents.17 The accumulating evidence favors Physiological Role the idea that in the rheumatoid joint, an- The physiological role of the prosta tigen(s) combining with antibody(s) ac glandins is not clear. They appear to be al tivates the complement sequence generating most ubiquitous, having been identified in a variety of biologically active materials in many tissues, each of which has the capacity cluding some with potent chemotactic prop erties. These bring polymorphonuclear leu C00H C0 cocytes (PMN) into the articular cavity where they are attracted to and ingest the C01 immune complexes. After phagocytosis, the ( dikomo-y-1ino1«nic acid) neutrophiles discharge, from their lysosomal

Figure 2. PGE and F compounds derive from fatty granules, a variety of hydrolytic enzymes. It acids. PGA and B compounds arise from PGE. is these substances that appear to be the 278 ZURIER direct cause of the proliferative and destruc inflammatory reaction does not, of course, tive changes characteristic of rheumatoid permit conclusions to be drawn about its im arthritis.3536 Similarly, muscle wasting portance in the pathogenesis of the lesion. caused by a variety of factors is accompanied However, the prostaglandins clearly seem by an increased activity of lysosomal acid able to function as mediators of inflam hydrolases, perhaps released from invading mation and anti-inflammatory compounds inflammatory cells. This occurs in muscular such as aspirin and indomethacin reduce dystrophy and polymyositis.23 prostaglandin synthesis in a dose-related Phagocytic cells release prostaglandins13 manner.30’32 and it has been suggested that lysosomal Although there is strong experimental evi phospholipases hydrolyze phospholipids of dence that prostaglandins are local media cell membranes to yield fatty acids. These tors of inflammation, effects on mediator re are in turn presumably converted to prosta lease which suggest anti-phlogistic actions glandins by freely available enzymes (prosta have also been described. Thus, PGE com glandin synthetase). There is evidence that pounds, which increase levels of cAMP in prostaglandins do, in fact, participate in the human leucocytes,28 reduce extrusion of development of the inflammatory re lysomal enzymes from viable human leu sponse.41 It is, therefore, not surprising that cocytes in vitro,*0 prevent release of his such inflammatory diseases as rheumatoid tamine and slow reacting substance of arthritis and polymyositis have served as anaphylaxis (SRS-A) from basophiles and common interest to students both of muscu lung fragments20 and prevent lymphocyte- loskeletal pathophysiology and the prosta mediated cytotoxicity.12 PGEj and E2 also glandins. suppress adjuvant-induced arthritis39 and The prostaglandins are capable of in cartilage destruction in rats38 and cAMP ducing the four cardinal signs of inflam treatment suppresses acute and chronic mation: redness, swelling, heat and pain. In inflammation in several experimental addition, PGE compounds increase pain models.15 These data suggest that PGE com sensitivity to other chemical mediators9 pounds, perhaps acting via cAMP, may in (bradykinin, histamine), and the injection of hibit as well as mediate acute and chronic PGE! or PGE2 into knee joints of dogs results inflammation. in a severe disabling arthritis.27 Later phases of induced inflammation are PGE! is chemotactic for rabbit PMN16 associated with increments in the concen suggesting that released prostaglandins tration of prostaglandin E2 in the inflamma might help perpetuate the inflammatory tory exudate.1 It is possible that as their reaction by calling forth additional leu concentration increases to approach “ phar cocytes. Explants of synovium obtained at macologic” levels locally, prostaglandins surgery from patients with rheumatoid may retard inflammation. A regulatory arthritis and maintained in organ culture, effect of prostaglandins is not without produce larger amounts of prostaglandin precedent in other systems. For example, al than synovium from patients with osteo though it is known that the prostaglandins arthritis.26 The prostaglandin-like substance are anti-lipolytic,4 the lipolytic hormones associated with several experimental models will increase prostaglandin formation in adi of inflammation appear to be terminal me pose tissue of certain species,29 suggesting diators of the acute response and it has been that the endogenous prostaglandins may suggested that the prostaglandins might be serve to attenuate hormonal stimulation of responsible, at least in part, for the transition lipolysis. Such effects appear to be mediated from an acute to chronic inflammatory le by cAMP. A similar example of autoregu sion.7 The presence of a substance in an lation is provided by the studies of PROSTAGLANDINS IN SKELETAL AND MUSCULAR DISORDERS 279

Hedqvist11 who has shown that PGE! and E2 compounds. For example, PGF2a inhibits the inhibit the release of noradrenalin from the increases in vascular permeability induced in spleen in response to sympathetic nerve skin by PGE, and E2.6 The formation of both stimulation. PGE2 is released by the spleen compounds follows a common pathway when it contracts in response to nerve until the final stage of biosynthesis and there stimulation. Thus, by a feedback mech is no evidence for interconversion between E anism, the contracting smooth muscle can and F prostaglandins. Local control of reduce the stimulus which is leading to the inflammation might therefore result from contraction. Prostaglandin release may, the preferential biosynthesis of one or therefore, be a defense mechanism5 aimed at another of the prostaglandins. minimizing potential injury. Pertinent to a view of prostaglandins as local regulators of Conclusions the inflammatory response is the ob servation15 that whereas large amounts of The mere presence of a substance does not cAMP (500 mg per kg daily x 5 days) reduce necessarily denote a physiological role, but the size of preformed granulomata, smaller the ubiquitous nature of the prostaglandins amounts of cAMP (1 or 10 mg per kg daily x and their remarkable potency suggest they 5 days) increase the size of granulomata in have an important function. There is evi rats. In addition, whereas the capacity of dence they participate in the development PGE! to suppress IgE dependent antigen-in- and possibly the modulation of inflammation duced release of histamine from human lung in man. Inflammation and tissue damage tissue appears owing to enhancement by may result from immune (hypersensitivity) PGEi of cellular cAMP, low concentrations reactions. That pharmacologic doses of of PGEi, which decrease cAMP levels, prostaglandins influence the immune re enhance histamine release.31 Treatment of sponse again suggests a possible regulatory rats with PGE] and PGE2 also inhibits the function. It does not seem unreasonable to IgE mediated release of SRS-A in a dose consider that either prostaglandin analogues response fashion.18 PGEj inhibits lym or prostaglandin antagonists or specific com phocyte-mediated destruction of alloge binations of both types of compounds may neic cells in vntro,12 suggesting an effect on become important adjuncts to treatment of T-lymphocytes. However, it is also capable immune-inflammatory musculoskeletal dis of reducing the humoral antibody response37 eases. Indeed, aspirin and indomethacin, and appears to prolong homograft survival both inhibitors of prostaglandin synthesis, through an effect on B-cells.24 Moreover, have long been mainstays in the manage there is experimental evidence that PGEi in ment of patients with inflammatory joint hibits release of antibodies from splenic disease. The effects of prostaglandins on the cells.21 Consequently, it is riot clear whether immunological and inflammatory responses PGE compounds act as “immunosup are varied, but further studies of their syn pressants” of T or B cells (or both) or thesis, metabolism and effects should make whether, in pharmacologic concentrations, their functions, if not completely clear, then they inhibit release of several cell products at least harmoniously confused. such as mediators of inflammation and/or antibodies. References Alternatively, or additionally, the prosta 1. ANDERSON, A. J., BROCKLEHURST, W. E., and glandins may serve to restrain the inflamma W ILLIS, A. L. : Evidence for the role of lysosomes tory response, not by means of a feedback in the formation of prostaglandins during carrageenan-induced inflammation in the rat. Pharm. mechanism but through a prescribed Res. Commun. 3.13-18, 1971. balance in local concentrations of E and F 2. BERGSTROM, S. and SJOVALL, J: The isolation 2 8 0 ZURIER

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