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Possible role of inducible nitric oxide synthase in articular chondrocytes in the pathogenesis of arthritic swelling.

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LETTERS
laboratory for use in the serum of transplant recipients (4),
but has not been sufficiently validated for BAL.
Thus, CMV pneumonia in our patient was mainly a
clinical diagnosis in the absence of evidence of MTX toxicity
(criteria not fulfilled). The condition resolved after a very
short course of steroids and after discontinuation of MTX.
We think that the latter allowed the patient’s own immune
system to become active again and to eliminate the pulmonary infection. We consider it important that patients receiving low-dose MTX who develop respiratory symptoms
should be followed up for the possible development of CMV
or non-CMV pulmonary infections because MTX may have
a greater immunosuppressive effect than previously thought.
This is supported by the recent results obtained by Wascher
et a1 (5) (from our institution), who demonstrated a cell-typespecific effect of parenterally administered low-dose MTX
on peripheral blood lymphocytes. This may cause a clinically important susceptibility to infections in patients who
receive MTX.
Ferdinand Aglas, MD
Franz Rainer, MD
Josef Hermann, MD
Judith Gretler, MD
Elisabeth Hiittl, MD
Wolfgang Domej, MD
Guenter J. Krejs, MD
Karl Franzens University
Graz, Austria
1. Searles G, McKendry RJR: Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors; four case reports and a
review of the literature. J Rheumatol 14: 1164-1 171, 1987
2. Carson CW, Cannon GW, Egger MJ, Ward JR, Clegg DO:
Pulmonary disease during the treatment of rheumatoid arthritis
with low dose pulse methotrexate. Semin Arthritis Rheum 16:
186-195, 1987
3. Geppert TD: Methotrexate as an anti-inflammatory agent: hope
or hype. Medical Grand Rounds, University of Texas Southwestern Medical Center, June 23:l-31, 1994
4. Halwachs G, Zach R, Pogglitsch H, Holzer H, Tiran A, Iberer P,
Wasler A, Tscheliessnigg HP, Lanzer G, Folsch B: A rapid
immunocytochemical assay for CMV detection in peripheral
blood of organ-transplanted patients in clinical practice. Transplantation 56:338-342, 1993
5 . Wascher TC, Hermann J, Brezinschek HP, Wilders-Truschnig
M, Rainer F, Krejs GJ: Cell-type specific response of peripheral
blood lymphocytes to methotrexate in the treatment of rheumatoid arthritis. Clin Invest 72535-540, 1994
Possible role of inducible nitric oxide synthase in
articular chondrocytes in the pathogenesis of arthritic
swelling
To the Editor:
In previous studies of the role of nitric oxide (NO) in
arthritic human joints (1,2), inflammatory and immunologic
mechanisms, cytotoxicity, and reactive oxygen species (3)
were emphasized more than vasodilatation. We suggest that
the bulk of the nitrite found in synovial fluid (SF) originated
from inducible NO synthase in chondrocytes rather than
from inflamed tissue (1,2); this would be consistent with
some aspects of joint morphology, metabolism, and physiology.
Joint cartilage is avascular. Fuel from the synovial
capillaries reaches cartilage primarily by convection in S F
(4). Sub-capsular synovial vessels supplying articular structures (synovium, cartilage, and some epiphyseal bones) are
1529
potential targets of joint tamponade (3). The distribution of
the capillaries in the synovial intima (5) and the surface areas
of a model knee (6) suggest that 96.6% of the volume of
tissue supplied by the synovial capillaries is cartilage. It
appears that cartilage cellularity is low, but chondrocyte
mass may be 3 times the mass of synovial intimal cells (7).
In cartilage, the rate of glycolysis is high under
aerobic conditions, and it is not clearly enhanced by hypoxia
(6,8). Low glucose levels enhance the formerly underrated
consumption of 0, (the Crabtree effect) (9). This regulation
of glucose oxidation (ATP yield 18 times that of glycolysis)
may explain the energy supply in deep chondrocytes (9).
Thus, high lactate in S F (10) need not reflect hypoxia,
whereas the presence of ketone bodies in (possibly hypoxic)
rheumatoid S F (10) is consistent with a hypothesis of oxidation of lipids (63). If consumption by tissues supplied by the
synovial capillaries (6) is recalculated (from refs. 5 and 9),
then cartilage emerges as a major consumer not only of glucose
but, at normal and subnormal glucose levels, also of 0,.
At arthroscopy of traumatized knee joints (1 l), we
determined plasma and SF colloid osmotic pressures
(COPplasmaand COPsf), and S F hydrostatic pressure (Psf;
range 4-61 mm Hg, normally negative); however, we did not
determine the fourth Starling pressure, capillary pressure
(Pea ill;reported averages 15 and 24 mm Hg). The difference
in tge hydrostatic pressures, Pcapill- PSf, tends to drive
filtering of fluid from plasma into normal joints, whereas the
effective part of the COP difference, COPplasma- COP,,
(averages 12 and 18 mm Hg), tends to hold most of the fluid
back (4). Therefore, simple arithmetic in this study would
must have been elevated,
suggest that, in most joints, Pcapill
otherwise a “back-suck” effect (i.e., net pressure from plasma
into S F negative) would have resorbed the effusions, and
arthroscopy would not have been performed (11).
The Pca ill may have been raised by post-capillary
tamponade, (1 lfwhich, however, would decrease blood flow
(4). Arteriolar dilatation, compensating for the effects of
tamponade by increasing the arteriolar pressure and Pcaplll,
could explain the “Starling deficit” (11) as well as the
occurrence of reactive hyperemia (3) and increased blood
flow in effusions (3,4,11). Furthermore, the correlation of SF
hypercapnia and acidosis (hypoxia not reliable in plastic
syringes) with PSfwas consistent with metabolic vasodilatation (1 l), possibly mediated by such factors (12). It was hard
to see how these changes around deep chondrocytes could
dilatate “their” arterioles in the synovium after passage
through better-supplied cartilage layers and SF. Therefore,
we suspected NO to be involved in this process (I 1).
The “novel” expression of inducible NO synthase
by chondrocytes (1) suggests that nitrite in SF may stem not
only from inflamed tissue (2) but also from cartilage. If the
synthase is induced by poor energy supply and, furthermore,
if inactivation of NO by oxidation is decreased by hypoxia,
the findings (1,2,3,11) would be consistent. This might also
explain the presence of nitrite in osteoarthritis (2), in which
inflammation is seldom prominent. Arteriolar dilatation not
only increases blood flow and the supply of fuel and oxygen
to tissues (12) but, by increasing mean Pcapil,,it also increases fluid escape from plasma (4,12). Synovial vasodilatation, possibly meeting cartilage energy demands following
low-pressure joint swelling and weak tamponade, may increase, as a byproduct, S F volume and P,,, thus aggravating
the joint swelling (11).
This proposal is falsifiable, as defined by the late Sir
Karl Popper (13); Le., it is misleading (false) if that part of
the resting angle PSfwhich is in excess of pressures attrib-
LETTERS
1530
utable to a decrease in effective COP differences or lymph
flow, or attributable to poorly resorbable matter, does not
correlate with increased synovial Pcapilland arteriolar vasodilatation. Part of the proposal is false if such “excess” P,,
does not correlate with former, current (NO, for example),
or eventual mediators of metabolic vasodilatation.
Johan Ahlqvist, MD
Sibbvik
Vastanfiard, Finland
Kaj Osterlund, PhD
University of Helsinki
Helsinki, Finland
1. Stefanovic-Racic M, Stadler J, Evans CH: Nitric oxide and
arthritis. Arthritis Rheum 36:10361044, 1993
2. Farrell AJ, Blake DR, Palmer RMJ, Moncada S: Increased
concentrations of nitrite in synovial fluid and serum samples
suggest increased nitric oxide synthesis in rheumatic diseases.
Ann Rheum Dis 51:1219-1222, 1992
3. Blake DR, Unsworth J, Outhwaite JM, Moms CJ, Merry P,
Kidd BL, Ballard R, Gray L, Lunec J: Hypoxic-reperfusion
injury in the inflamed human joint. Lancet 1:289-293, 1989
4. Levick JR: Blood flow and mass transport in synovial joints. In,
Handbook of Physiology, Volume IV: Cardiovascular System.
Microcirculation (part 2). Edited by EM Renkin, CC Michel.
Bethesda, MD, American Physiological Society, 1984
5. Stevens CR, Blake DR, Merry P, Revel1 PA, Levick JR: A
comparative study by morphometry of the microvasculature in
normal and rheumatoid synovium. Arthritis Rheum 3 4 15081513, 1991
6. Ahlqvist J, Harilainen A, Osterlund K: Does joint cartilage
require energy? (letter). Ann Rheum Dis 48:878, 1989
7. Levick JR: Microvascular architecture and exchange in synovial joints (abstract). Int J Microcirc Clin Exp 14:241, 1994
8. Dunham J, Dodds RA, Nahir AM, Frost GTB, Catterall A,
Bitensky L, Chayen J: Aerobic glycolysis of bone and cartilage:
the possible involvement of fatty acid oxidation. Cell Biochem
Func 1:168-172, 1983
9. Otte P: Basic cell metabolism of articular cartilage: manometric
studies. Z Rheumatol 50:304-312, 1 9 9 1
10. Naughton DP, Haywood R, Blake DR, Edmonds S, Hawkes
GE, Grootveld M: A comparative evaluation of metabolic
profiles of normal and inflammatory knee-joint synovial fluids
by high resolution proton NMR spectroscopy. FEBS Lett
332:221-225, 1993
1 1 . Ahlqvist J, Harilainen A, Aalto K, Sarna S, Lalla M, Osterlund
K: High hydrostatic pressures in traumatic joints require elevated synovial capillary pressure probably associated with
arteriolar vasodilatation. Clin Physiol 14:671479, 1994
12. Renkin EM: Control of microcirculation and blood-tissue exchange. In, Handbook of Physiology, Volume IV: Cardiovascular System. Microcirculation (part 2). Edited by EM Renkin,
CC Michel. Bethesda, MD, American Physiological Society, 1984
13. Popper KR: The Logic of Scientific Discovery. Tenth impression. London, Hutchinson, 1980
Reply
To the Editor:
Drs. Ahlqvist and Osterlund observe that although
chondrocytes respire glycolytically under both aerobic and
anaerobic conditions, they nevertheless consume large
amounts of oxygen. Because cartilage is avascular, chondrocytes depend upon synovial perfusion to meet this oxygen
demand; large effusions have the potential to compromise
the chondrocyte’s oxygen supply by causing synovial tam-
ponade. These authors offer the ingenious speculation that
chondrocytes solve this problem by producing NO, which
dilates synovial arterioles. They note that this is ultimately a
self-defeating mechanism because it also leads to larger
effusion volumes. It is further pointed out that although
cartilage cellularity is low, the volume of articular cartilage is
such that the chondrocyte mass in joints is higher than most
investigators appreciate. Therefore, chondrocytes may be a
major intraarticular source of NO in joints.
We agree with the authors’ conclusion that the
articular chondrocytes are a major source of NO in joints.
Articular chondrocytes produce as much, if not more, NO
per cell than synoviocytes, ligament cells, or even macrophages. Moreover, the work of Rediske et a1 (1) suggests
that, of the tissues present in human joints, only articular
chondrocytes are readily capable of expressing inducible
nitric oxide synthase (iNOS). This is in contrast to tissues
from rabbit joints, which, in addition to chondrocytes (2),
synovial fibroblasts (3), ligament cells, and meniscal cells
(Evans CH, Stefanovic-Racic M: unpublished observations),
can be easily provoked into synthesizing high levels of NO.
When considering the consequences of NO production by cartilage, most attention has been paid to possible
autocrine responses. Nevertheless, as Ahlqvist and Osterlund point out, NO could also act in a paracrine manner on
adjacent tissues such as the synovial arterioles. The vasodilatory properties of NO are undisputed. Indeed, one route
to the discovery of NO as a physiologic mediator was its
designation as an “endothelium-derived relaxing factor” (4,5).
Thus, the NO produced by articular chondrocytes
certainly could dilate blood vessels in the adjacent synovium. Whether this actually happens in vivo requires
further study. Enthusiasm for the authors’ hypothesis,
which is partly derived from manometric data obtained
during arthroscopy of traumatized knees, should be tempered by the results of a recent study in which we failed to
detect evidence of elevated NO synthesis in traumatized
human joints (Evans CH, Stefanovic-Racic M: unpublished
observations).
Dilatation of the synovial arterioles need not necessarily lead to larger effusions, as the authors fear. For
instance, in one study, treadmill exercise increased by 7-fold
the synovial blood flow in canine wrists without producing
discernible effusions (6). Thus, increased fluid exudation
probably necessitates that NO also produce permeability
changes in the synovial microvasculature. There has been
some evidence of this (for example, see ref. 7), but more
studies need to be done in this area.
It is ditficult to comment in detail on the energy
metabolism of chondrocytes, as lamentably little is known
about this topic. Indeed, the 1937 paper by Bywaters (8) is
still frequently cited. Chondrocytes are generally assumed to
respire anaerobically not only because the oxygen tension of
cartilage is very low, but also because chondrocytes continue to favor glycolysis even when oxygen is not limiting.
This being so, the lactate acidosis that occurs in inflamed
joints need not necessarily result from a further drop in
oxygen tension, as is commonly assumed. Interleukin-1, for
example, increases lactate production by articular chondrocytes 3-5-fold under conditions of constant oxygen tension.
Interestingly, this increase is largely dependent upon NO (9).
If chondrocytes show this reluctance to metabolize
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inducible, oxide, nitric, arthritis, role, possible, pathogenesis, swelling, synthase, articular, chondrocyte
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