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.
osteoclast activity (12–14). The effect of leptin defi-
ciency on stromal cells is to increase the production of
osteoblasts while decreasing differentiation of marrow
adipocytes (15). Leptin deficiency is associated with low
total bone mass due primarily to decreased cortical bone
formation via the hypothalamus signal pathway (16). In
contrast, trabecular bone mass may be increased, as
observed in the original studies of the ob/ob mouse by
Ducy and colleagues (17), in which they primarily inves-
tigated the spine, a trabecular bone. Overall, when total
bone mass is evaluated, the contribution from the higher
cortical bone mass of the skeleton (80%) masks the
contribution from the lower mass of trabecular bone
(20%). Interestingly, this difference between cortical
and trabecular bone may be a phenomenon observed
only in mice, because patients with low leptin levels due
to anorexia show low bone mass and density throughout
the skeleton (18).
A few studies have addressed the role of leptin in
cartilage metabolism. Simopoulou and colleagues inves-
tigated the expression of leptin by chondrocytes and
observed an increase in leptin messenger RNA in chon-
drocytes from obese individuals; the increase was not
correlated with slightly damaged cartilage but rather,
was correlated with advanced OA (19). Leptin treatment
of chondrocytes was proinflammatory and catabolic,
inducing production of IL-1?, matrix metalloproteinase
9 (MMP-9), and MMP-13. Otero and colleagues showed
that costimulation of chondrocytes with leptin and IL-1
or interferon increased the expression of inducible nitric
oxide synthase and increased nitric oxide production,
thus mediating down-regulation of matrix synthesis and
up-regulation of MMP activity (20). In contrast, leptin
has anabolic effects in cartilage in that it stimulates 2
growth factors, transforming growth factor ? and
insulin-like growth factor 1 (21). Thus, in cartilage, the
question is whether leptin is pro-degenerative or pro-
Other adipokines produced in adipose tissue may
also contribute to the onset and progression of cartilage
degeneration. One such adipokine is resistin. Resistin
was originally identified in mice as an adipokine that
might provide the link between obesity and insulin
resistance (22); levels of both resistin and leptin are
elevated in obese individuals. Resistin is produced by
adipose tissue and monocyte/macrophages but also by
cartilage itself, and is a very powerful proinflammatory
cytokine, increasing production of IL-1, TNF?, and
various chemokines (23). Following traumatic joint in-
jury, resistin levels are increased, causing matrix degra-
dation and release of inflammatory cytokines from ar-
ticular cartilage; therefore, resistin may play a role quite
different from that of leptin.
The relationship between obesity and OA is an
important public health issue. The average body weight
of elderly individuals has steadily risen in recent years
and, in younger age groups, longitudinal data have
shown that obesity is a powerful risk factor for the
development of knee OA (3). One twin study revealed a
9–13% increased risk of OA onset with every kilogram
increase in body weight (24). There is certainly reason to
believe that the incidence of obesity-related knee OA
will increase over the next 25 years. The effects of weight
loss were examined in an analysis of randomized con-
trolled trials that measured changes in pain and function
when overweight patients with knee OA achieve weight
loss (5). Weight reduction of at least 7.5% at a rate of at
least 0.6% per week was predicted to result in a moder-
ate clinical effect. If the general dietary approaches to
reducing body weight are applied, using a rate of weight
loss of 0.5–1.5 kg/week, the meta-analysis shows that a
10% weight reduction will result in a moderate-to-large
clinical effect on disability.
To date, the relationship between obesity, weight
loss, and OA is far from clear. The study reported in this
issue of Arthritis & Rheumatism indicates that leptin
could be involved in OA, because without leptin, obesity
did not predispose to OA (1). Earlier studies showed
that obesity in normal mice leads to OA (25); in the
current study, however, no standard was set for the
degree of OA in obese mice without leptin mutations as
control. In addition, the link between joint loading and
obesity is problematic in these mice, because they do not
bear much weight on their legs, but rather on their
It will be very informative to conditionally knock
out leptin and other adipokines, such as resistin, in a
joint-, bone-, or cartilage-specific manner, because when
mice develop without leptin, as in the mutants used in
the study by Griffin et al, other events may take place
that affect overall physiology. It will also be interesting
to induce traumatic OA in leptin-knockout mice to
determine whether their response to injury is different
from that of normal mice on the C57BL/6J background
or another background that is more or less resistant to
OA. Investigating the response of cartilage and chon-
drocytes to leptin in the leptin-deficient mice would be
helpful, but these studies will remain for the future. In
contrast to such changes in genetically deficient mice,
changing levels of leptin and obesity in “normal” mice
may help to shed light on the complex relationship
between obesity and OA. For certain, the role of leptin
in physiology and metabolism is a balancing act, with
local and systemic factors playing a role, as pointed out
by Loeser in 2003 (27). Via the study conducted by
Griffin and colleagues (1), one more piece of the puzzle
is put in place, however; without leptin, mice appear to
be protected from OA. Thus, the balance is tipped to a
pro-degenerative function for leptin in cartilage.
1. Griffin TM, Huebner JL, Kraus VB, Guilak F. Extreme obesity
due to impaired leptin signaling in mice does not cause knee
osteoarthritis. Arthritis Rheum 2009;60:2935–44.
2. Hamrick MW. Leptin and bone: a consensus emerging? BoneKEy-
3. Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF.
Obesity and knee osteoarthritis: the Framingham Study. Ann
Intern Med 1988;109:18–24.
4. Hart DJ, Spector TD. Cigarette smoking and risk of osteoarthritis
in women in the general population: the Chingford study. Ann
Rheum Dis 1993;52:93–6.
5. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight
reduction in obese patients diagnosed with knee osteoarthritis: a
systematic review and meta-analysis. Ann Rheum Dis 2007;66:
6. Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD.
The role of knee alignment in disease progression and functional
decline in knee osteoarthritis. JAMA 2001;286:188–95.
7. Dequeker J, Mohan S, Finkelman RD, Aerssens J, Baylink
DJ. Generalized osteoarthritis associated with increased insulin-
like growth factor types I and II and transforming growth factor ?
in cortical bone from the iliac crest: possible mechanism of
increased bone density and protection against osteoporosis. Ar-
thritis Rheum 1993;36:1702–8.
8. Powell A, Teichtahl AJ, Wluka AE, Cicuttini FM. Obesity: a
preventable risk factor for large joint osteoarthritis which may act
through biomechanical factors. Br J Sports Med 2005;39:4–5.
9. Jackson BD, Teichtahl AJ, Morris ME, Wluka AE, Davis SR,
Cicuttini FM. The effect of the knee adduction moment on tibial
cartilage volume and bone size in healthy women. Rheumatology
10. Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver
Spring) 2006;14 Suppl 5:242–9S.
11. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman
JM. Positional cloning of the mouse obese gene and its human
homologue. Nature 1994;372:425–32.
12. Cornish J, Callon KE, Bava U, Lin C, Naot D, Hill BL, et al.
Leptin directly regulates bone cell function in vitro and reduces
bone fragility in vivo. J Endocrinol 2002;175:405–15.
13. Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG.
Leptin is a potent stimulator of bone growth in ob/ob mice. Regul
14. Elmquist JK, Strewler GJ. Physiology: do neural signals remodel
bone? Nature 2005;434:447–8.
15. Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL.
Leptin acts on human marrow stromal cells to enhance differen-
tiation to osteoblasts and to inhibit differentiation to adipocytes.
16. Thomas T. The complex effects of leptin on bone metabolism
through multiple pathways. Curr Opin Pharmacol 2004;4:295–300.
17. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT,
et al. Leptin inhibits bone formation through a hypothalamic relay:
a central control of bone mass. Cell 2000;100:197–207.
18. Turner JM, Bulsara MK, McDermott BM, Byrne GC, Prince RL,
Forbes DA. Predictors of low bone density in young adolescent
females with anorexia nervosa and other dieting disorders. Int J
Eat Disord 2001;30:245–51.
19. Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N, Papa-
theodorou L, Ioannou M, et al. Differential expression of leptin
and leptin’s receptor isoform (Ob-Rb) mRNA between advanced
and minimally affected osteoarthritic cartilage: effect on cartilage
metabolism. Osteoarthritis Cartilage 2007;15:872–83.
20. Otero M, Lago R, Lago F, Reino JJ, Gualillo O. Signalling
pathway involved in nitric oxide synthase type II activation in
chondrocytes: synergistic effect of leptin with interleukin-1. Ar-
thritis Res Ther 2005;7:R581–91.
21. Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P,
et al. Evidence for a key role of leptin in osteoarthritis. Arthritis
22. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright
CM, et al. The hormone resistin links obesity to diabetes. Nature
23. Lee JH, Ort T, Ma K, Picha K, Carton J, Marsters PA, et al.
Resistin is elevated following traumatic joint injury and causes
matrix degradation and release of inflammatory cytokines from
articular cartilage in vitro. Osteoarthritis Cartilage 2009;17:
24. Cicuttini FM, Baker JR, Spector TD. The association of obesity
with osteoarthritis of the hand and knee in women: a twin study.
J Rheumatol 1996;23:1221–6.
25. Silberberg R. Obesity and joint disease. Gerontology 1976;22:
26. Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000;62:413–37.
27. Loeser RF. Systemic and local regulation of articular cartilage
metabolism: where does leptin fit in the puzzle? [editorial].
Arthritis Rheum 2003;48:3009–12.