Effects of 1-hydroxyethylidene-1,1 bisphosphonate and (chloro-4 phenyl) thiomethylene bisphosphonic acid (SR 41319) on the mononuclear cell factor-mediated release of neutral proteinases by articular chondrocytes and synovial cells

doi:10.1016/0006-2952(85)90385-5

Biochemical Pharmacology

Volume 34, Issue 22, 15 November 1985, Pages 4043-4049

https://doi.org/10.1016/0006-2952(85)90385-5 Get rights and content

Abstract

Articular chondrocytes and synovial cells were stimulated to produce collagenase, neutral casein and proteoglycan-degrading proteinases by conditioned medium from human peripheral blood mononuclear cells. Collagenase, neutral casein and proteoglycan-degrading proteinase secretion was inhibited by SR 41319, a new bisphosphonate, in a concentration-dependent manner. Complete inhibition was achieved at about 0.3 mM. EHDP exhibited the same general profile but was about 10-fold less active and never completely inhibited the enzyme secretion. When added before MCF, SR 41319 had a protective effect against subsequent activation of the cells by MCF. SR 41319 also inhibited the increase of enzyme secretion by cells previously stimulated with MCF.

The results suggest that the ability of SR 41319 to inhibit the MCF-mediated secretion of neutral enzymes involved in cartilage destruction could be valuable in the management of connective tissue damage in rheumatoid arthritis.

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Cited by (32)

Bisphosphonates: Pharmacology and clinical approach to their use in equine osteoarticular diseases
2014, Journal of Equine Veterinary Science
Citation Excerpt :
In recent articles, the use of BPs as metalloproteinase inhibitors has been suggested [77–79], and it has been demonstrated that in vitro tiludronate can inhibit the activity of matrix metalloproteinases (MMP-1 and MMP-3), thus supporting the idea that one of the mechanisms by which BPs accomplish their effect is by chelating cations that are used as enzyme cofactors [80]. In another in vitro study [81], tiludronate was able to inhibit the interleukin (IL) 1–mediated secretion of cartilage matrix–degrading enzymes by chondrocytes and synovial cells. In a dog anterior cruciate ligament transaction model follow by reconstructive surgery, the cartilage volume loss was greatly prevented and concomitant treatment with tiludronic acid provided an additional benefit reducing experimental OA lesions [82].
Bisphosphonates (BPs) are drugs widely used in various bone diseases, mainly for their skeletal antiresorptive effect. Nowadays, they are also used to treat degenerative pathologies such as arthritis because of their particular anti-inflammatory and analgesic properties. Since the sixties, BPs with different characteristics and biological activity profiles have been studied, although most of the pharmacologic and clinical trials have been carried out in humans. By 2002, however, tiludronate was granted a marketing license in France for use in horses. The objective of this article is to review the literature available on BPs and apply this knowledge, either experimentally or clinically, to equine osteoarticular disease therapy.
Pharmacotherapy of joint and tendon disease
2013, Equine Sports Medicine and Surgery: Second Edition
Extra-skeletal effects of bisphosphonates
2007, Joint Bone Spine
Citation Excerpt :
BPs stimulate chondrocyte proliferation in rabbits [55] and induce direct metabolic chondrocyte alterations, such as increased synthesis of collagen and proteoglycans, as described in several studies [56]. Chloro-4-phenyl-thiomethylene bisphosphonate (SR 41319) and, to a lesser extent, etidronate inhibit the secretion of several matrix metalloproteinases (MMPs), such as collagenase, proteinase acting on caseine, and proteoglycans, from joint chondrocytes and synoviocytes stimulated by macrophage colony-stimulating factor (MCS-F) [57]. Pamidronate and risedronate inhibit apoptosis and growth impairment induced by dexamethasone in cultured chondrocytes suggesting a chondroprotective effect of the amino-BPs during corticosteroid treatment [58].
Bisphosphonates are pharmacological agents which are currently used both in osteoporosis than in other pathological conditions characterised by an increased bone resorption, such as Paget's disease of bone, malign hypocalcaemia during myeloma, osteolytic bone metastasis and fibrous dysplasia of bone. The most important biological effect of bisphosphonates is the reduction of bone remodelling through the inhibition of osteoclastic activity, but there are many clinical and experimental evidences of extra-skeletal biological effects of bisphosphonates. It has been shown that bisphosphonates exert their effects not only on bone tissue cells, but also on those of the immune system with an “immuno-modulating” effect, influencing the production of pro- and anti-inflammatory cytokines and changing the molecular expression involved in the immune processes and anti-inflammatory response. Although the available data are conflicting, there are several reports concerning the beneficial effects of bisphosphonates in controlling the progression of chronic joint inflammatory diseases, suggesting a wider use for these therapeutic agents in clinical practice.
Extra-skeletal effects of bisphosphonates<sup>{lozenge, open}</sup>{lozenge, open}Pour citer cet article, utiliser ce titre en anglais et sa référence dans le même volume de Joint Bone Spine.
2007, Revue du Rhumatisme (Edition Francaise)
Les bisphosphonates sont utilisés pour traiter non seulement l'ostéoporose, mais aussi d'autres pathologies caractérisées par une résorption osseuse accrue, comme la maladie de Paget, l'hypercalcémie maligne du myélome, les métastases osseuses lytiques et la dysplasie fibreuse des os. Le principal effet biologique des bisphosphonates consiste en une réduction du remodelage osseux liée à une inhibition de l'activité des ostéoclastes. Toutefois, de nombreuses observations cliniques et expérimentales montrent que les bisphosphonates ont des effets extraosseux. Par exemple, en dehors de leur action sur les cellules osseuses, les bisphosphonates exercent un effet immunomodulateur sur les cellules immunitaires, influençant ainsi la production de cytokines pro- et anti-inflammatoires et modifiant l'expression des molécules qui participent aux phénomènes immunitaires et à la réponse anti-inflammatoire. Bien que les données soient contradictoires, plusieurs études décrivent un effet favorable des bisphosphonates sur l'évolution des rhumatismes inflammatoires chroniques, laissant penser que les indications cliniques de ces molécules pourraient s'étendre prochainement.
The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage
2002, Osteoarthritis and Cartilage
Objective The purpose of this work was to test the effect of inhibition of bone remodeling, through the use of the bisphosphonate, zoledronic acid, on cartilage matrix damage in an animal model of cartilage matrix damage.
Design New Zealand white rabbits were divided into four groups for treatment purposes: (1) untreated controls; (2) injected into one knee joint with the cartilage matrix degradation enzyme, chymopapain; (3) injected into one knee joint with chymopapain and also given subcutaneous injections of the bisphosphonate, zoledronic acid, three times per week until sacrifice at either day 28 or 56 post-chymopapain-injection; (4) received only the zoledronic acid injections. At sacrifice, the knee joints were examined grossly and histologically, and biochemically for proteoglycan content. Urine samples were analysed, at intervals, for levels of collagen cross-links which are biochemical markers of cartilage and bone.
Results Animals receiving both intraarticular chymopapain injections and subcutaneous zoledronic acid injections displayed a significantly lower degree of grossly and histologically detectable cartilage degeneration on the tibial articular surfaces (the articular surface displaying the greatest degree of degeneration) than did animals only receiving the chymopapain injections. In addition, urinary levels of collagen cross-links for bone and cartilage were significantly higher in those animals only receiving chymopapain injections.
Conclusion The bone resorption observed after chymopapain injection into the rabbit knee joint can be inhibited through the use of the bisphosphonate, zoledronic acid. Furthermore, zoledronic acid does not increase the level of cartilage degeneration and appears to provide some level of chondroprotection in this model.
The role of bisphosphonates in the treatment of painful metastatic bone disease: A review of phase III trials
1998, Pain
Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour-induced hypercalcemia, Paget's disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients' compliance, are well-tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.

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Biochemical Pharmacology

Effects of 1-hydroxyethylidene-1,1 bisphosphonate and (chloro-4 phenyl) thiomethylene bisphosphonic acid (SR 41319) on the mononuclear cell factor-mediated release of neutral proteinases by articular chondrocytes and synovial cells

Abstract

Biochim. biophys. Acta

Biochem. Pharmac.

Analyt. Biochem.

Analyt. Biochem.

J. Biochem. Biophys. Meth.

Biochem. Pharmac.

Lymphokines

Ann. Rheum. Dis.

Agents Actions

Scand. J. Rheumatol. (Suppl.)

Agents Actions

Scand. J. Rheumatol. (Suppl.)

Arthritis Rheum.

Clin. exp. Immun.

J. Rheumat. (Suppl.)

J. Rheumat.

Ann. Rheum. Dis.

Calc. Tiss. Res.

Arthritis Rheum.

Experientia

Bisphosphonates: Pharmacology and clinical approach to their use in equine osteoarticular diseases

Pharmacotherapy of joint and tendon disease

Extra-skeletal effects of bisphosphonates

Extra-skeletal effects of bisphosphonates<sup>{lozenge, open}</sup>{lozenge, open}Pour citer cet article, utiliser ce titre en anglais et sa référence dans le même volume de Joint Bone Spine.

The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage

The role of bisphosphonates in the treatment of painful metastatic bone disease: A review of phase III trials