Besides its primary function in locomotion, skeletal muscle (SKM), which represents up to half of human's weight, also plays a fundamental homeostatic role. Through the secretion of soluble peptides, ...or myokines, SKM interacts with major organs involved in metabolic processes. In turn, metabolic cues from these organs are received by muscle cells, which adapt their response accordingly. This is done through an intricate intracellular signaling network characterized by the cross-talking between anabolic and catabolic pathways. A fine regulation of the network is required to protect the organism from an excessive energy expenditure. Systemic inflammation evokes a catabolic reaction in SKM known as sarcopenia. In turn this response comprises several mechanisms, which vary depending on the nature of the insult and its magnitude. In this regard, aging, chronic inflammatory systemic diseases, osteoarthritis and idiopathic inflammatory myopathies can lead to muscle loss. Interestingly, sarcopenia may persist despite remission of chronic inflammation, an issue which warrants further research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) system stands as a major participant in muscle loss during systemic inflammation, while it is also a well-recognized orchestrator of muscle cell turnover. Herein we summarize current knowledge about models of sarcopenia, their triggers and major mediators and their effect on both protein and cell growth yields. Also, the dual action of the JAK/STAT pathway in muscle mass changes is discussed. We highlight the need to unravel the precise contribution of this system to sarcopenia in order to design targeted therapeutic strategies.
Objective
To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis ...(OA).
Methods
A multicenter, randomized, double‐blind, placebo‐controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate‐to‐severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100‐mm visual analog scale VAS). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)–Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy.
Results
Intriguingly, in the modified intent‐to‐treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months −11.8 ± 2.4 mm 19% reduction in patients receiving CS plus GS versus −20.5 ± 2.4 mm 33% reduction in patients receiving placebo; peak between‐group difference in global pain score at 6 months 8.7 mm 14.2%, P < 0.03), but no between‐group differences were seen in the per‐protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per‐protocol completers. Neither the OMERACT–OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed.
Conclusion
The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.
Osteoarthritis treatment should contemplate the improvement of subchondral bone quality. This therapeutic approach must be individualized in each patient depending on the BMD status and the ...physiopathological subgroup of osteoarthitis (OA). BMD: bone mineral density; SB: subchondral bone.
Osteoarthritis (OA), the most common form of arthritis, is a debilitating and progressive disease that has become a major cause of disability and impaired quality of life in the elderly. OA is considered an organ disease that affects the whole joint, where the subchondral bone (SB) plays a crucial role. Regardless of whether SB alterations precede cartilage damage or appear during the evolution of the disease, SB is currently recognised as a key target in OA treatment. In fact, bone abnormalities, especially increased bone turnover, have been detected in the early evolution of some forms of OA. Systemic osteoporosis (OP) and OA share a paradoxical relationship in which both high and low bone mass conditions may result in induction and/or OA progression. Recent findings suggest that some drugs may be useful in treating both processes simultaneously, at least in a subgroup of patients with OA and OP. This review focuses on the role of SB in OA pathogenesis, describing relevant underlying mechanisms involved in the process and examining the potential activity as disease-modifying anti-osteoarthritic drugs (DMOADs) of certain SB-targeting agents currently under study.
Osteoarthritis (OA) affects all articular tissues and finally leads to joint failure. Although articular tissues have long been considered unresponsive to estrogens or their deficiency, there is now ...increasing evidence that estrogens influence the activity of joint tissues through complex molecular pathways that act at multiple levels. Indeed, we are only just beginning to understand the effects of estrogen deficiency on articular tissues during OA development and progression, as well as on the association between OA and osteoporosis. Estrogen replacement therapy and current selective estrogen receptor modulators have mixed effectiveness in preserving and/or restoring joint tissue in OA. Thus, a better understanding of how estrogen acts on joints and other tissues in OA will aid the development of specific and safe estrogen ligands as novel therapeutic agents targeting the OA joint as a whole organ.
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Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, osteophyte formation, subchondral bone sclerosis, and synovitis. Systemic factors such as ...obesity and the components of the metabolic syndrome seem to contribute to its progression. Breakdown of cartilage ensues from an altered balance between mechanical overload and its absorption by this tissue. There is in this context a status of persistent local inflammation by means of the chronic activation of innate immunity. A broad variety of danger-associated molecular patterns inside OA joint are able to activate pattern recognition receptors, mainly TLR (toll-like receptor) 2 and 4, which are overexpressed in the OA cartilage. Chronic activation of innate immune responses in chondrocytes results in a robust production of pro-inflammatory cytokines and chemokines, as well as of tissue-destructive enzymes, downstream of NF-κB and MAPK (mitogen activated protein kinase) dependent pathways. Besides, the toxic effects of an excess of glucose and/or fatty acids, which share the same pro-inflammatory intracellular signalling pathways, may add fuel to the fire. Not only high concentrations of glucose can render cells prone to inflammation, but also AGEs (advanced glycation end products) are integrated into the TLR signalling network through their own innate immune receptors. Considering these mechanisms, we argue for the control of both primary inflammation and proteolytic catabolism as a preventive strategy in OA, instead of focusing treatment on the enhancement of anabolic responses. Even though this approach would not return to normal already degraded cartilage, it nonetheless might avoid damage extension to the surrounding tissue.
Multinucleated giant cells have been noticed in diverse arthritic conditions since their first description in rheumatoid synovium. However, their role in the pathogenesis of osteoarthritis (OA) or ...rheumatoid arthritis (RA) still remains broadly unknown. We aimed to study the presence and characteristics of multinucleated giant cells (MGC) both in synovium and in subchondral bone tissues of patients with OA or RA.
Knee synovial and subchondral bone samples were from age-matched patients undergoing total joint replacement for OA or RA, or non-arthritic post mortem (PM) controls. OA synovium was stratified by histological inflammation grade using index tissue sections. Synovitis was assessed by Krenn score. Histological studies employed specific antibodies against macrophage markers or cathepsin K, or TRAP enzymatic assay.
Inflamed OA and RA synovia displayed more multinucleated giant cells than did non-inflamed OA and PM synovia. There was a significant association between MGC numbers and synovitis severity. A TRAP negative/cathepsin K negative Langhans-like subtype was predominant in OA, whereas both Langhans-like and TRAP-positive/cathepsin K-negative foreign-body-like subtypes were most commonly detected in RA. Plasma-like and foam-like subtypes also were observed in OA and RA synovia, and the latter was found surrounding adipocytes. TRAP positive/cathepsin K positive osteoclasts were only identified adjacent to subchondral bone surfaces. TRAP positive osteoclasts were significantly increased in subchondral bone in OA and RA compared to PM controls.
Multinucleated giant cells are associated with synovitis severity, and subchondral osteoclast numbers are increased in OA, as well as in RA. Further research targeting multinucleated giant cells is warranted to elucidate their contributions to the symptoms and joint damage associated with arthritis.
Introduction
Dental implant osseointegration can be impaired in medical conditions with low bone mass, such as glucocorticoid‐induced osteoporosis. Intermittent human parathyroid hormone (PTH) 1‐34 ...administration has shown relevant anabolic bone activity in various animal models of osteoporosis. Therefore, we studied the effects of intermittent PTH 1‐34 on bone response around titanium implants in experimental osteoporosis induced by ovariectomy and glucocorticoid administration.
Methods
Titanium dental implants were placed in the proximal tibia metaphysis in 38 animals. Twenty‐eight rabbits had undergone bilateral ovariectomy and further methylprednisolone administration for 4 weeks to induce osteoporosis. Ten healthy rabbits were used as controls. At week 8, osteoporotic rabbits started saline vehicle or intermittent PTH administration for 12 weeks. Bone mineral density (BMD) was assessed in peri‐implant area, lumbar spine, and global and subchondral knee bone at baseline, and weeks 6 and 20. Animal sacrifice was carried out at week 21. Afterward, tibiae were removed for μCT morphometry and undecalcified sections were evaluated by light and scanning electron microscopy.
Results
PTH increased bone‐to‐implant contact compared with control rabbits or vehicle administration in osteoporotic rabbits (P < 0.005). PTH‐induced new bone formation around external and internal surfaces of titanium implants led to a significant increase of BMD at peri‐implant area in osteoporotic rabbits at week 20, when compared with vehicle (P < 0.005). Likewise, PTH increased BMD in other analysed regions.
Conclusions
Intermittent administration of PTH 1‐34 enhances the bone response around titanium implants in a rabbit model of ovariectomy and glucocorticoid‐induced osteoporosis.
The identification of well-defined phenotypes along the course of the disease may open new avenues for personalized management in osteoarthritis (OA). In vivo research carried out in various animal ...models as well as epidemiological and clinical data support the existence of a particular phenotype - osteoporotic OA. In fact, subchondral bone has become a potential therapeutic target in OA. Depending on the ratio between formation and resorption, subchondral bone remodeling can culminate in either a sclerotic or an osteoporotic phenotype. Patients with osteoporotic OA may thus achieve clinical and structural benefit from treatment with bone-targeted interventions.
Highlights • Osteoarthritisis the most common chronic joint disorder and its prevalence increases rapidly during midlife. • The complex nature of the relationships between numerous factors involved ...in the etiopathogenesis makes difficult the identification of osteoarthritisis phenotypes. • An adequate stratification of patients with osteoarthritisis into particular phenotypes could optimize the design of individualized treatments. • Four well-defined clinical phenotypes are proposed in osteoarthritisis: biomechanical, osteoporotic, metabolic and inflammatory.
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