Modulation of insulin-like growth factor 1 levels in human osteoarthritic subchondral bone osteoblasts
Introduction
Osteoarthritis (OA) is a common leading cause of morbidity in the aging population and is characterized by cartilage degradation and loss, osteophyte formation, and subchondral bone plate thickening. Although numerous investigations have focused their efforts on understanding cartilage homeostasis, the etiology of this disease remains elusive. It is now accepted to consider the joint as an organ and OA as a disease of this organ. The cartilage is not the only tissue affected in this pathology. The subchondral bone and synovial tissues are also involved in OA. Indeed, recent data indicate a role of the subchondral bone in the onset and/or progression of this disease [1], [2], [3]. This is related to an abnormal cellular metabolism of OA subchondral osteoblasts (Ob) as demonstrated by altered phenotypic markers and abnormal production of cytokines and growth factors [1], [4], [5]. Moreover, two populations of patients can be discriminated based on the production of both prostaglandin E2 (PGE2) and interleukin-6 (IL-6) by isolated Ob, whereas no clinical signs of OA presently used to classify these patients could discriminate them [5]. Of note, a similar observation was also reported by Tardif et al. using isolated chondrocytes from normal and OA individuals and their response to IL-1 challenge [6], and a recent report using synovial cells indicated differences in inflammatory response in early and late OA patients with indications that cyclooxygenase-2 (COX-2) expression, responsible for PGE2 synthesis, was different between the two groups [7]. Hence, restricted biological signals can discriminate two populations of OA individuals. Regardless of this classification, in OA, the activation of Ob leading to bone sclerosis causes increased stress to the overlying cartilage and produces factors influencing cartilage metabolism [3], [8]. Thus, understanding the mechanisms leading to bone sclerosis is of the utmost importance in the treatment of OA.
Insulin-like growth factor 1 (IGF-1) is a predominant growth factor produced by Ob. It is a strong mitogenic agent that promotes Ob differentiation and collagen type I production and protects bone matrix degradation by matrix metalloproteases [9]. As IGF-1 production is increased in OA Ob compared to normal Ob, it is a likely candidate to promote bone sclerosis in OA [1]. Bone IGF activity can be regulated at multiple levels [10]. In particular, IGF synthesis and/or release by skeletal tissue may be altered by a variety of growth regulators. It is well known that, in Ob cell models, both parathyroid hormone (PTH) and PGE2 can up-regulate IGF-1 mRNA levels and that cAMP serves as the intracellular second signal [11], [12], [13], [14], [15].
Differential expression and local synthesis of specific IGF binding proteins (IGFBPs) may control the amount of IGFs available for binding to specific IGF receptors [9]. Osteoblasts can synthesize at least the first six IGFBPs, although to variable extents, depending on the particular cell culture system and conditions. In bone tissue, three IGFBPs appear to be of major importance for the modulation of IGF-1, IGFBP-3 and -4, which generally have inhibitory effect on bone, and IGFBP-5, which stimulates bone formation [9]. Moreover, both the IGFs and IGFBPs may be stabilized by their association, limiting their sensitivity to proteolytic degradation [10].
Rhodopsin-type receptors mediate the action of prostaglandins, and four subtypes of PGE2 receptors designated EP1, EP2, EP3, and EP4 are encoded by different genes and expressed differently in each tissue [16], [17], [18], [19]. Each receptor subtype triggers a specific intracellular signaling pathway; EP1 is coupled to Ca2+ mobilization, EP3 inhibits adenylate cyclase, whereas both EP2 and EP4 stimulate adenylate cyclase [20], [21], [22]. EP1, EP2, and EP4 receptors have been previously shown to play a role in osteoblasts, whereas a role for EP3 in osteoblasts is unlikely [23], [24], [25], [26], [27].
As we recently demonstrated that the production of PGE2 and IL-6 by OA Ob can separate OA patients into two subgroups, namely, the low and the high producers, in which the high OA group produces PGE2 and IL-6 levels two- to six-fold above normal values, whereas the low OA group produces normal PGE2 and IL-6 levels [5], the scope of this study was to determine if IGF-1 production by both OA Ob subgroups is different and to discriminate the mechanisms responsible for the increased IGF-1 production.
Section snippets
Patients and clinical parameters
All human materials were acquired following a signed agreement by patients undergoing knee surgery or by relatives for specimens collected at autopsy following the CHUM ethical committee guidelines. The subchondral bone plate from tibial plateaus of OA patients who had undergone total knee replacement surgery was dissected under sterile conditions. A total of forty patients (aged 70 ± 9 years, mean ± SD: 16 males/24 females) classified as having OA according to recognized ACR clinical criteria
Production of IGF-1 in OA and normal culture media
We recently demonstrated that two metabolic activities of subchondral Ob, namely PGE2 and IL-6 production, can distinguish two subgroups of OA patients. In one subgroup, subchondral Ob produced PGE2 and IL-6 levels comparable to normal and were classified as low producers and in the other subgroup Ob produced higher levels and were classified as high producers [5], [36], [37]. Here, we performed a first series of experiments to evaluate the endogenous levels of IGF-1 produced by these subgroups
Discussion
The variable IGF-1 levels noted in OA Ob compared to normal reproduced our previous data [1] and discriminated two populations of OA patients as we previously observed with PGE2, interleukin-6 and leukotriene B4 [5], [38]. As both the low and the high OA Ob subgroups showed an increase in IGF-1 levels compared to normal Ob, this difference could be partly explained by endogenous PGE2 levels produced by OA Ob. Indeed, a direct relationship between endogenous levels of PGE2 and the production of
Acknowledgments
We wish to thank Mrs. Aline Delalandre for her technical assistance on this project. D. Lajeunesse is a Chercheur National from the “Fonds de la Recherche en Santé du Québec”. F. Massicotte is the recipient of a Ph.D. studentship from the “Groupe de Recherche en Transport Membranaire” from the Université de Montréal. This study was supported by grant MOP-49501 from the Canadian Institutes for Health Research to DL.
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