ARTHRITIS & RHEUMATISM
Vol. 60, No. 10, October 2009, pp 2858–2860
© 2009, American College of Rheumatology
Obesity and Osteoarthritis: Is Leptin the Link?
Linda J. Sandell
There is significant interest in the correlation
between adipose regulators of metabolism, inflamma-
tion, and the occurrence of osteoarthritis (OA). In this
issue of Arthritis & Rheumatism, Griffin and colleagues
report the results of their investigation of the role of
leptin (1). The investigators hypothesized that obesity in
mice resulting from deletion of the leptin gene (ob/ob)
or deletion of the leptin receptor gene (db/db) would
result in an increased incidence of knee OA, systemic
inflammation, and altered subchondral bone morphol-
ogy. In both of these mouse strains, adiposity was
increased by ?10-fold compared with controls. Surpris-
ingly, the incidence of OA was not higher in ob/ob and
db/db mice than in the control background strain,
These results suggest that obesity alone does not
cause OA. However, other changes occurred in these
mice due to the loss of leptin function. Leptin-deficient
mice had reduced subchondral bone thickness and in-
creased relative trabecular bone volume in the tibial
epiphysis, as previously reported (for review, see ref. 2).
An extensive analysis of inflammatory molecules was
carried out by Luminex bead assay, which revealed an
increased level of only interleukin-8 (IL-8) and thus not
an overall inflammatory effect of leptin deficiency.
These results imply that leptin may be involved in the
development of OA. Without leptin, adiposity is insuf-
ficient to induce systemic inflammation and knee OA,
suggesting a potential role of leptin itself in regulating
skeletal and immune functions.
OA is strongly correlated with a high body mass
index (3,4), and weight loss is correlated with decreased
progression of OA (5). Clearly, biomechanical factors
impact the relationship between obesity and OA.
Sharma and colleagues (6) have demonstrated that an
altered knee angle in obese patients influences the risk
of progression of knee OA. A role of bone has also been
speculated, in that obesity increases subchondral bone
stiffness, making bone less adept at coping with impact
loads (7,8). The increased stiffness of bone may subse-
quently redistribute a greater force across the underlying
articular cartilage, increasing its vulnerability to degen-
erative changes (9). Although biomechanics parameters
are important, OA is more common in women and exists
in non–weight-bearing joints such as the hand, indicating
that a metabolic component is also present.
In addition to increasing body weight, body fat
(white adipose tissue) secretes a large variety of peptides
and is actually now considered to be an endocrine organ
(10). Some of these peptides, such as leptin and adi-
ponectin, were initially characterized as regulators of
metabolism and were subsequently shown to modulate
inflammatory processes as well. Other peptides are
well-known cytokines, such as IL-6, IL-1? and its recep-
tor antagonist, and tumor necrosis factor ? (TNF?).
Leptin is the 16-kd nonglycosylated protein prod-
uct of the obese (ob) gene, which was discovered by
cloning the mutated gene present in a strain of very
obese mice (11). Mice lacking production of functional
leptin or lacking functional leptin receptors have a
phenotype resembling that of humans with morbid
obesity. Leptin appears to act centrally by stimulating
receptors present in the hypothalamus to regulate food
intake and energy expenditure. Plasma levels of leptin
correlate very closely with fat mass, and leptin levels fall
after weight loss (11).
Leptin has also emerged as the major factor
linking food intake with bone metabolism (2), although
the relationship is complex. Fat cells are the primary
source of leptin. Leptin enters the circulation and
crosses the blood–brain barrier to reach its primary
target, the hypothalamus. Circulating leptin also regu-
lates bone mass directly by binding to leptin receptors on
bone marrow stromal cells, osteoblasts, and osteoclasts,
functioning to increase osteoblast activity and decrease
Linda J. Sandell, PhD: Washington University School of
Medicine, St. Louis, Missouri.
Address correspondence and reprint requests to Linda J.
Sandell, PhD, Department of Orthopaedic Surgery, Washington Uni-
versity School of Medicine at Barnes-Jewish Hospital, 660 South
Euclid Avenue, Box 8233, St. Louis, MO 63110. E-mail: sandelll@
Submitted for publication June 9, 2009; accepted in revised
form June 29, 2009.