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Anti-inflammatory Effects of Topical Formulations Containing Sea Silt and Sea Salt on Human Skin In vivo During Cutaneous Microdialysis

Authors:
  • Helix Medical Excellence Center Mainz

Abstract

Silt is sediment formed in estuaries and coastal regions along the seashore. It occurs along the entire North Sea coast and it is used in skin therapy. A single mud treatment induces normalization of stratum corneum hydration, transepidermal water loss, skin surface pH and sebum content (1). Mud therapy has been used successfully in several inflammatory skin diseases, such as psoriasis vulgaris (2), atopic dermatitis (3), acne vulgaris (4) and skin ulcers (5). The aim of this study was to elucidate possible anti-inflammatory effects of sea silt and sea salt-containing topical formulations on human skin in vivo. MATERIALS AND METHODS Different topical formulations containing sea silt essences and sea salt were tested: La mer MED Sea-salt cream ® (SSC, 7.5% sea silt, 10% sea salt), La mer MED sea salt lotion ® (SSL, 5% sea silt, 3.5% sea salt) and La mer MED fat cream ® (FC, 7.5% sea silt, 0.5% sea salt) (La mer, Cuxhaven, Germany). The silt extract in these formulations contains approximately 0.6% fatty acids (hexadecanoic acid, hexadecenoic acid, eico-sapentaenoic acid, octadecatrienoic acid and eicosatetraenoic acid) and 0.3% sulphur. All formulations (except for SSL) also contain 1% hydrolysed enteromorpha compressa extract and up to 5% hydrogenated vege table and palm kernel oil, which contains 82% saturated and 18% unsaturated fatty acids (i.e. oleic acid and linoleic acid). Twenty healthy volunteers aged 22–29 years were tested for tolerability and efficacy of sea silt formulations after approval by the local ethics committee. To test tolerability, ten healthy volunteers (age range 22–27 years) applied SSC to one-half of the body's skin surface (either left or right). In addition, five volunteers applied SSL to one side of the body and FC to the other half; the head and back were left as untreated control areas. After 2 h, skin areas on the left and right upper and lower arms, legs and back were measured for skin pH, transepidermal water loss (TEWL) (Derma Unit SSC3 and Tewameter TM300, both from Courage & Khazaka, Cologne, Germany) and skin colour (Chromameter CR-300, Minolta, Osaka, Japan) (6, 7). Measurements were repeated 0.5 h and 24 h after irradiation with a minimal erythematous dose (MED) of ultraviolet A (UVA) and ultraviolet B (UVB) (Waldmann UV 3003K, Herbert Waldmann GmbH & Co. KG, Villingen-Schwenningen, Germany). To test anti-inflammatory efficacy, well-defined areas of 9 cm 2 on the volar forearms of 10 healthy volunteers (age range 23–29 years) were exposed to UVB irradiation with twice the minimal erythematous dose (450–550 mJ/cm 2), followed by treatment with test formula-tions, diclofenac gel (DG, Voltaren Emulgel ® , Novartis AG, Nuremberg, Germany) or base cream (BC, a cream composed primarily of water, paraffin, citric acid, sodium cetearyl sulphate and cetearyl alcohol; Laticort base cream ® , Almirall Hermal, Reinbek, Germany) as a negative control. Two hours after ir-radiation, a thin layer of each formulation (approximately 500 mg) covering the entire test area was applied six times every 2 h and gently rubbed in for approximately 5 min until it was absorbed. Cut-off membranes of 20 kDa (CMA71 60/20 mem-branes, CMA microdialysis, Sweden) were placed in the dermis at 0.7–1.2 mm depth, as determined by 22 MHz ultrasound (taberna pro medicum, Luneburg, Germany) and cutaneous mi-crodialysis was started 24 h after UVB irradiation in irradiated and treated skin as well as in non-irradiated and untreated skin as described earlier (8). After flushing the membranes at a rate of 5 µl/min for 1 h for equilibration, membranes were perfused at a flow rate of 0.5 µl/min with sodium chloride (NaCl) 0.9%, using a CMA107 microdialysis pump (CMA Microdialysis, Solna, Sweden). Microdialysate samples were collected at 30-min intervals for 8 h and analysed for 5-and 8-iso-PGF 2α F 2 -isoprostanes and 9α,11α-PGF 2α and PGE 2 prostaglandins using sensitive gas chromatography-mass spectrometry and negative ion chemical ionization, as described previously (8). Since it has been demonstrated previously that the intensity of skin erythema correlates with levels of prostanoids (9), skin darkness and erythema of all test areas were measured at the end of microdialysis, 36 h after UVB irradiation in six volunteers (Chromameter CR-300, Minolta, Osaka, Japan). Mean values, standard errors (SE), significance (Wilcoxon signed-rank test) and area under the curve (AUC) were calculated with MedCalc 10 (MedCalc, Mariakerke, Belgium).
Acta Derm Venereol 91
1
Letters to the Editor 2011 Epub ahead of print
© 2011 The Authors. doi: 10.2340/00015555-1128
Journal Compilation © 2011 Acta Dermato-Venereologica. ISSN 0001-5555
Silt is sediment formed in estuaries and coastal regions
along the seashore. It occurs along the entire North Sea
coast and it is used in skin therapy. A single mud treatment
induces normalization of stratum corneum hydration,
transepidermal water loss, skin surface pH and sebum
content (1). Mud therapy has been used successfully in
several inammatory skin diseases, such as psoriasis
vulgaris (2), atopic dermatitis (3), acne vulgaris (4) and
skin ulcers (5). The aim of this study was to elucidate
possible anti-inammatory effects of sea silt and sea salt-
containing topical formulations on human skin in vivo.
MATERIALS AND METHODS
Different topical formulations containing sea silt essences and
sea salt were tested: La mer MED Sea-salt cream® (SSC, 7.5%
sea silt, 10% sea salt), La mer MED sea salt lotion® (SSL,
5% sea silt, 3.5% sea salt) and La mer MED fat cream® (FC,
7.5% sea silt, 0.5% sea salt) (La mer, Cuxhaven, Germany).
The silt extract in these formulations contains approximately
0.6% fatty acids (hexadecanoic acid, hexadecenoic acid, eico-
sapentaenoic acid, octadecatrienoic acid and eicosatetraenoic
acid) and 0.3% sulphur. All formulations (except for SSL) also
contain 1% hydrolysed enteromorpha compressa extract and
up to 5% hydrogenated vege table and palm kernel oil, which
contains 82% saturated and 18% unsaturated fatty acids (i.e.
oleic acid and linoleic acid). Twenty healthy volunteers aged
22–29 years were tested for tolerability and efficacy of sea silt
formulations after approval by the local ethics committee. To
test tolerability, ten healthy volunteers (age range 22–27 years)
applied SSC to one-half of the body’s skin surface (either left
or right). In addition, five volunteers applied SSL to one side
of the body and FC to the other half; the head and back were
left as untreated control areas. After 2 h, skin areas on the left
and right upper and lower arms, legs and back were measured
for skin pH, transepidermal water loss (TEWL) (Derma Unit
SSC3 and Tewameter TM300, both from Courage & Khazaka,
Cologne, Germany) and skin colour (Chromameter CR-300,
Minolta, Osaka, Japan) (6, 7). Measurements were repeated
0.5 h and 24 h after irradiation with a minimal erythematous
dose (MED) of ultraviolet A (UVA) and ultraviolet B (UVB)
(Waldmann UV 3003K, Herbert Waldmann GmbH & Co. KG,
Villingen-Schwenningen, Germany). To test anti-inflammatory
efficacy, well-defined areas of 9 cm2 on the volar forearms of
10 healthy volunteers (age range 23–29 years) were exposed
to UVB irradiation with twice the minimal erythematous dose
(450–550 mJ/cm2), followed by treatment with test formula-
tions, diclofenac gel (DG, Voltaren Emulgel®, Novartis AG,
Nuremberg, Germany) or base cream (BC, a cream composed
primarily of water, paraffin, citric acid, sodium cetearyl sulphate
and cetearyl alcohol; Laticort base cream®, Almirall Hermal,
Reinbek, Germany) as a negative control. Two hours after ir-
radiation, a thin layer of each formulation (approximately 500
mg) covering the entire test area was applied six times every
2 h and gently rubbed in for approximately 5 min until it was
absorbed. Cut-off membranes of 20 kDa (CMA71 60/20 mem-
branes, CMA microdialysis, Sweden) were placed in the dermis
at 0.7–1.2 mm depth, as determined by 22 MHz ultrasound
(taberna pro medicum, Luneburg, Germany) and cutaneous mi-
crodialysis was started 24 h after UVB irradiation in irradiated
and treated skin as well as in non-irradiated and untreated skin
as described earlier (8). After flushing the membranes at a rate
of 5 µl/min for 1 h for equilibration, membranes were perfused
at a flow rate of 0.5 µl/min with sodium chloride (NaCl) 0.9%,
using a CMA107 microdialysis pump (CMA Microdialysis,
Solna, Sweden). Microdialysate samples were collected at
30-min intervals for 8 h and analysed for 5- and 8-iso-PGF
F2-isoprostanes and 9α,11α-PGF and PGE2 prostaglandins
using sensitive gas chromatography-mass spectrometry and
negative ion chemical ionization, as described previously (8).
Since it has been demonstrated previously that the intensity of
skin erythema correlates with levels of prostanoids (9), skin
darkness and erythema of all test areas were measured at the end
of microdialysis, 36 h after UVB irradiation in six volunteers
(Chromameter CR-300, Minolta, Osaka, Japan). Mean values,
standard errors (SE), significance (Wilcoxon signed-rank test)
and area under the curve (AUC) were calculated with MedCalc
10 (MedCalc, Mariakerke, Belgium).
RESULTS
All test products were well-tolerated without any side-
effects or increase in skin pigmentation throughout
the study (data not shown). All preparations prevented
a decrease in pH and an increase in transepidermal
Anti-inammatory Effects of Topical Formulations Containing Sea Silt and Sea Salt on Human Skin
In Vivo During Cutaneous Microdialysis
Sven R. Quist1, Ingrid Wiswedel2, Jennifer Quist1 and Harald P. Gollnick1
1Clinic of Dermatology and Venereology, and 2Department of Pathological Biochemistry, Otto-von-Guericke University, Magdeburg, Leipziger Str. 44, DE-
39120 Magdeburg, Germany. E-mail: squist@gmx.de
Accepted February 2, 2011.
Table I. Changes in skin pH, transepidermal water loss (TEWL in
g/m2 ∙ h) and skin erythema (values > 0 indicates increasing skin
erythema) at baseline (2-h treatment with topical formulations
containing sea silt and sea salt or untreated), 0.5 h, and 24 h after
ultraviolet A/ultraviolet B (UVA/UVB) irradiation (mean of 10
volunteers with standard error (SE))
Skin pH TEWL Erythema
Untreated skin
2 h treatment 5.15 ± 0.57 7.74 ± 0.19 9.92 ± 2.89
0.5 h post-UV 4.96 ± 0.13 7.74 ± 0.18 10.56 ± 0.35
24 h post-UV 5.14 ± 0.14 7.81 ± 0.26 11.73 ± 0.67
Fat cream
2 h treatment 5.00 ± 0.49 6.94 ± 0.22 10.65 ± 1.28
0.5 h post-UV 5.04 ± 0.45 6.97 ± 0.29 10.83 ± 1.22
24 h post-UV 5.30 ± 0.56 5.90 ± 0.4 11.16 ± 1.24
Sea salt cream
2 h treatment 5.11 ± 0.42 6.72 ± 0.19 10.10 ± 1.15
0.5 h post-UV 5.17 ± 0.40 7.59 ± 0.23 10.26 ± 0.75
24 h post-UV 5.28 ± 0.47 6.05 ± 0.32 11.06 ± 1.56
Sea salt lotion
2 h treatment 5.35 ± 0.26 6.75 ± 0.17 9.66 ± 1.16
0.5 h post-UV 5.42 ± 0.29 7.13 ± 0.15 9.78 ± 1.01
24 h post-UV 5.17 ± 0.42 5.22 ± 0.23 10.47 ± 1.49
2Letters to the Editor
water loss (TEWL) observed at 24 h post-UVA/UVB
in untreated skin (Table I). Furthermore, FC and SSL
strongly decreased TEWL and all sea silt preparations
inhibited increase in skin erythema 24 h post-UV
irradiation compared with untreated skin (Table I).
Microdialysis showed lower mean values of AUC for
8-iso-PGF
and total F2-isoprostanes, obtained from
dialysates of treated skin areas in all 10 volunteers with
any treatment compared with BC (Table II). Treatment
with DG resulted in lower amounts of mean AUC for
all markers, whereas treatment with SSL resulted in
lower amounts of mean AUC for 9α,11α-PGF
in all
10 volunteers tested. In six volunteers, we were able to
analyse changes in skin darkness and erythema of trea-
ted skin areas at the end of microdialysis 36 h after UVB
irradiation (Table III). There was a signicant decrease
in skin redness and darkness at 36 h for untreated non-
irradiated skin and skin treated with SSC, SSL and DG,
but not for FC compared with skin areas treated with BC
as a negative control (Table III). When comparing these
results with the mean values of AUC for 5- and 8-iso-
PGF2α, total F2-isoprostanes and 9α,11α-PGF2α and
PGE2 prostaglandins from the microdialysates of the
same volunteers, decreases were observed in untreated
non-irradiated skin and skin areas treated with the same
topical formulations; that is, SSL, SSC and DG.
DISCUSSION
We used cutaneous microdialysis to detect differences
in prostanoid levels of irradiated and treated skin. Ho-
wever, microdialysis is an invasive method (10), leading
to release of prostanoids. This, together with the small
number of patients, may have prevented the detection of
signicant differences between treatment areas, although
sufcient time was allowed for tissue recovery and
equilibration as determined in previous experiments (8,
11). Sea silt extract contains various active substances
from sea silt, such as unsaturated fatty acids, sulphur and
algae. These ingredients could contribute to sea silt’s anti-
inammatory efcacy, which are known to derive from
omega-3 and omega-6 fatty acids (12). Omega fatty acids
inhibit the formation of pro-inammatory eicosanoids,
but can also form potent anti-inammatory lipid medi-
ators, such as resolvins and protectins, suppress NFκB
activity and reduce the production of pro-inammatory
enzymes and cytokines (COX-2, TNF-α, IL-1β) (13).
We were able to demonstrate that all tested sea silt- and
sea salt-containing topical formulations suppressed the
UVB-provoked release of 8-iso PGF
, which is a well-
known marker of oxidative stress. Furthermore, skin
redness and skin darkening was signicantly decreased
by sea silt- and sea salt-containing formulations (more
for lotion than for cream). However, the effect was lower
than that observed following treatment with oral diclo-
fenac, a known inhibitor of COX-1 and -2. FC, the only
formulation that did not contain sea salt, failed to exert a
suppressive effect on prostanoids 9α,11α-PGF2α, PGE2
and 5-iso-PGF2α.
ACKNOWLEDGEMENTS
We would like to thank Ines Doering for excellent technical
assistance. The study was supported by La mer cosmetic AG,
Cuxhaven, Germany.
Conflict of interest: Sven R Quist received financial support
from La mer cometics AG for materials (microdialysis cathe-
ters and topical formulations) in order to conduct this trial. No
further conflict of interest by any of the author is reported.
REFERENCES
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Table II. Prostanoid levels presented as area under the curve (AUC; mean values in pg/ml ∙ h ± standard error (SE)) from microdialysates of
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Acta Derm Venereol 91
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Letters to the Editor
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Acta Derm Venereol 91
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SUMMARY Report OBJECTIVE Longtime mud therapy (pelotherapy) is a therapeutic technique that is widely used throughout Europe, mainly in Spas, Thermal Centers and Rehabilitation Centers, for the treatment of different rheumatologic processes (rheumatism, osteoarthritic degenerative, inflammatory processes etc.) and some dermatological diseases, such as psoriasis, which have excellent medical results and, lately, also cosmetic. This report describes the specific technique used in each pathology, the properties of the elements or raw materials included in the different types of peloids.Medical and cosmetic instructions, information technologies etc. There is a comprehensive study of systematic review carried out to find out scientific evidence of this technique, including for that purpose more than thousand seven hundred references. The therapeutic effects of Pelotherapy are not very-well known among the medical groups, being techniques used by medical specialists trained post-Bachelor hydrologists in the specialty, way MIR. This report intends to disseminate the new knowledge medical-therapeutics as a new therapeutic tool, of high efficiency and effectiveness. Medical groups can get more efficient results than using other drugs, being at the same time a non-aggressive technique and very well tolerated by all type of patients (rheumatism, dermatologists, with certain vascular pathologies or in processes of rehabilitation osteoarticular). Furthermore, the Pelotherapy is a technical that, could even be used in their own homes with the minimum training. JUSTIFICATION of the publication and interest It is an innovative report in medical therapy because of the lack of awareness about this technology as well as its feasible results. Its implementation could guess a reduction of pharmaceutical costs on healthcare system, getting the same or better efficacy and effectiveness than other products in the Pharmacopoeia, through the combination of physical and pharmacological therapies. The cost/effectiveness of the pelotherapy technology study is higher than other anti-inflammatory and analgesic products. The dissemination of this report is especially relevant for rehabilitation physicians, rheumatologists, dermatologists, IMSERSO and spas. This report describes likewise the properties of the different peloid types, the pathologies as well as the obtained results. METHODOLOGY This report has a multidisciplinary approach thanks to the participation of forty-four authors and collaborators, medical specialists (hydrologists), pharmacists, hydrogeologists, physiotherapists and nurses in order to achieve a better understanding. The authors, come from the autonomous regions of Andalusia, Galicia and Aragon as well as from Italy and Argentina. They are great experts of the Pelotherapy techniques and technologies The literature searching by chapters has been made independently by each author. The presentation of bibliographic repertory responds to a systematic order by subject, included at the end of each chapter. On this way, the consultation of bibliographical references is simplified, as his group corresponds to the specific topic consulted, providing bibliographic information on each type of condition. Within each chapter, the management of authors is alphabetical or sequential, according to their appearance in other issues, using the Vancouver standard nomenclature. It has been conducted a systematic search of the available scientific literature until the middle of 2012In order to analyse the volume and quality of the publications about Pelotherapy. The databases analysed are the following,:MEDLINE (PubMed), EMBASE, TRIP Database, The Cochrane Library (Cochrane database of systematic reviews and clinical trials)DARE (Database of Abstract of Reviews of Effects), NHS EED (Economic Evaluation Database) and HTA database (Health Technology Assessment) the Centre for Reviews and Dissemination (CRD) of the University of York, without restrictions of language or date in the recovery of the bibliographical references. The searching terms have been selected according to the characteristic of every thesaurus database. Different searching strategies are presented in the chapter on systematic reviews. RESULTS This report explains the techniques and medical technology used in Pelotherapy, describing all their instructions and applications according to the different complaints. . This report has taken two and a half years due to the issue and the large group of authors involved in.. 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Inflammation is a physiological response to tissue trauma or infection, but leukocytes, which are the effector cells of the inflammatory process, have powerful tissue remodelling capabilities. Thus, to ensure their precise localisation, passage of leukocytes from the blood into inflamed tissue is tightly regulated. Recruitment of blood borne neutrophils to the tissue stroma occurs during early inflammation. In this process, peptide agonists of the chemokine family are assumed to provide a chemotactic stimulus capable of supporting the migration of neutrophils across vascular endothelial cells, through the basement membrane of the vessel wall, and out into the tissue stroma. Here, we show that, although an initial chemokine stimulus is essential for the recruitment of flowing neutrophils by endothelial cells stimulated with the inflammatory cytokine tumour necrosis factor-alpha, transit of the endothelial monolayer is regulated by an additional and downstream stimulus. This signal is supplied by the metabolism of the omega-6-polyunsaturated fatty acid (n-6-PUFA), arachidonic acid, into the eicosanoid prostaglandin-D(2) (PGD(2)) by cyclooxygenase (COX) enzymes. This new step in the neutrophil recruitment process was revealed when the dietary n-3-PUFA, eicosapentaenoic acid (EPA), was utilised as an alternative substrate for COX enzymes, leading to the generation of PGD(3). This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD(2) receptor. Here, we describe a new step in the neutrophil recruitment process that relies upon a lipid-mediated signal to regulate the migration of neutrophils across endothelial cells. PGD(2) signalling is subordinate to the chemokine-mediated activation of neutrophils, but without the sequential delivery of this signal, neutrophils fail to penetrate the endothelial cell monolayer. Importantly, the ability of the dietary n-3-PUFA, EPA, to inhibit this process not only revealed an unsuspected level of regulation in the migration of inflammatory leukocytes, it also contributes to our understanding of the interactions of this bioactive lipid with the inflammatory system. Moreover, it indicates the potential for novel therapeutics that target the inflammatory system with greater affinity and/or specificity than supplementing the diet with n-3-PUFAs.
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The skin, it is well know, is an organ of frontier and it is natural seat to natch, or collition, between exogenous stimoli and endogenous responses. Termal water and spud mud revelead their better potency on the skin and for that their tird close attention in dermatology. Our primary pourpose was to evalue eventuals modifications induced by thermal water and mud on healty skin and to know how their alter in significative mode functionals parameters, an alteration of which characterising pathogenetics events in development of acne. They are: follicular keratinisation, sebum synthesis by sebaceum glands, skin inflammation, loss of gate function of epidermidis. Results are showed.
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Magnesium salts, the prevalent minerals in Dead Sea water, are known to exhibit favorable effects in inflammatory diseases. We examined the efficacy of bathing atopic subjects in a salt rich in magnesium chloride from deep layers of the Dead Sea (Mavena(R) Dermaline Mg(46) Dead Sea salt, Mavena AG, Belp, Switzerland). Volunteers with atopic dry skin submerged one forearm for 15 min in a bath solution containing 5% Dead Sea salt. The second arm was submerged in tap water as control. Before the study and at weeks 1-6, transepidermal water loss (TEWL), skin hydration, skin roughness, and skin redness were determined. We found one subgroup with a normal and one subgroup with an elevated TEWL before the study. Bathing in the Dead Sea salt solution significantly improved skin barrier function compared with the tap water-treated control forearm in the subgroup with elevated basal TEWL. Skin hydration was enhanced on the forearm treated with the Dead Sea salt in each group, which means the treatment moisturized the skin. Skin roughness and redness of the skin as a marker for inflammation were significantly reduced after bathing in the salt solution. This demonstrates that bathing in the salt solution was well tolerated, improved skin barrier function, enhanced stratum corneum hydration, and reduced skin roughness and inflammation. We suggest that the favorable effects of bathing in the Dead Sea salt solution are most likely related to the high magnesium content. Magnesium salts are known to bind water, influence epidermal proliferation and differentiation, and enhance permeability barrier repair.
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Several studies have demonstrated that matrix metalloproteinases (MMPs) are frequently implicated in the destruction of articular cartilage in arthritis. The control of MMP activity is dependent on the local concentration of tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the enzyme-to-inhibitor ratios plays an important role in the remodeling of articular tissues. Some cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha which regulate leukocyte activities, promote MMP secretion and, as a consequence, cartilage degradation. The aim of the present study was to investigate whether a natural treatment is effective in reducing cartilage inflammation and degradation by influencing MMP and TIMP serum levels. Eighty patients with osteoarthritis (OA) were enrolled in the trial and were divided into group A (30 patients who did not undergo mud bath therapy), group B (28 patients repeating mud bath therapy more than 5 times and less than 10) and group C (22 patients repeating mud bath therapy more than 10 times). Blood samples were obtained from all the patients for assay of MMP-1, -2, -3, -8 and -9 and TIMP-1 and -2. The parameters were determined by an ELISA technique. Statistical indexes were calculated for each parameter and mean values were compared. The differences between mean values of MMP-3, -8 and -9 were statistically significant between group A and the treated groups (B and C). Analysis of variance established a significant difference (p < 0.05) between groups A and C in mean serum levels of MMP-8, MMP-9 showed a statistically significant difference (p < 0.05) in mean serum concentration between groups A and B. Regression analysis showed a very high R2 between MMP-2 and TIMP-2. One of the most interesting findings in this study was that MMP-3 serum levels were significantly lower in the treated groups, since this enzyme plays an important role in cartilage degradation, suggesting that mud bath therapy contributes to matrix integrity in OA cartilage. In contrast, MMP-8 and -9 were higher in the treated subjects and no correlation with TIMPs was evident. One possible explanation is that these enzymes are required for the efficient degradation and removal of already compromised cartilage matrix and that they operate as part of a matrix turnover and repair process. In conclusion, our data suggest that mud bath therapy alone is not able to influence chondrocyte metabolic activity in the advanced phases of OA. There could be a synergic and sequential association with pharmacologic therapy and/or interventions.