Rheumatol Int DOI 10.1007/s00296-015-3251-z
Rheumatology INTERNATIONAL
REVIEW ARTICLE - PATHOLOGY REVIEW
TGF‑β signal transduction pathways and osteoarthritis Guangju Zhai1 · Jules Doré1 · Proton Rahman1
Received: 7 November 2014 / Accepted: 9 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Osteoarthritis (OA) is the most common form of arthritis, resulting in substantial disability and economic burden worldwide. While its exact pathogenesis remains elusive, both in vitro and human population-based studies have merged to support the hypothesis that TGF-β/BMPmediated signalling pathways play a role in the development of OA. Unraveling the TGF-β/BMP-mediated mechanism(s) in OA has great potential in identifying novel targets and developing new drugs for OA treatment. This review summarizes both in vitro and in vivo evidence of TGF-β/BMP-mediated signal transduction pathways in OA and discusses the future research direction in this regard. Keywords Osteoarthritis · TGF-β signalling pathways · SMAD · BMP
Introduction Osteoarthritis (OA) is characterized pathologically by focal areas of damage to the articular cartilage, centered on loadbearing areas, associated with new bone formation at the joint margins (osteophytosis), changes in the subchondral bone, variable degrees of mild synovitis, and thickening of the joint capsule [1]. It primarily involves the joints of the knee, hip, spine, hand, and foot and is strongly associated with increasing age. It is the most common form of arthritis, results in substantial morbidity and disability in
* Guangju Zhai [email protected] 1
Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Canada
the elderly [2], and imposes a great economic burden on society [3]. This societal burden (both in terms of personal suffering and use of healthcare resources) is expected to increase worldwide due to the increasing prevalence of obesity and aging of the community [4]. Despite high prevalence and societal impact, OA’s etiology and pathogenesis remain elusive, which are impediments to developing effective preventative therapies and easing the condition’s symptoms. Although the etiology of OA is not fully understood, it is believed that a number of different environmental and genetic factors interact to cause its initiation and progression [5]. It is also recognized that OA is a heterogeneous group of diseases with different pathogenesis in different joints [6]. Age is the strongest risk factor for all joint OA, while obesity appears to confer the greatest risk of knee OA, particularly in women [7]. Twin studies suggest a strong genetic predisposition to hand and hip OA, with a heritability estimate of over 64 % [8, 9]. Genetic effects on knee OA are modest with a heritability of 39 % [8], but significant for knee OA progression, with a heritability of over 69 % [10]. This has led to vigorous effort and huge investment by the research community into identifying specific OA genes. Presently, there are at least 10 genome-wide association studies (GWAS) [11], resulting in 15 genetic loci that have achieved GWAS significance level [12]. It appears that these OA-associated genetic factors are joint specific and have only modest effects with an odds ratio of
Rheumatology INTERNATIONAL
REVIEW ARTICLE - PATHOLOGY REVIEW
TGF‑β signal transduction pathways and osteoarthritis Guangju Zhai1 · Jules Doré1 · Proton Rahman1
Received: 7 November 2014 / Accepted: 9 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Osteoarthritis (OA) is the most common form of arthritis, resulting in substantial disability and economic burden worldwide. While its exact pathogenesis remains elusive, both in vitro and human population-based studies have merged to support the hypothesis that TGF-β/BMPmediated signalling pathways play a role in the development of OA. Unraveling the TGF-β/BMP-mediated mechanism(s) in OA has great potential in identifying novel targets and developing new drugs for OA treatment. This review summarizes both in vitro and in vivo evidence of TGF-β/BMP-mediated signal transduction pathways in OA and discusses the future research direction in this regard. Keywords Osteoarthritis · TGF-β signalling pathways · SMAD · BMP
Introduction Osteoarthritis (OA) is characterized pathologically by focal areas of damage to the articular cartilage, centered on loadbearing areas, associated with new bone formation at the joint margins (osteophytosis), changes in the subchondral bone, variable degrees of mild synovitis, and thickening of the joint capsule [1]. It primarily involves the joints of the knee, hip, spine, hand, and foot and is strongly associated with increasing age. It is the most common form of arthritis, results in substantial morbidity and disability in
* Guangju Zhai [email protected] 1
Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Canada
the elderly [2], and imposes a great economic burden on society [3]. This societal burden (both in terms of personal suffering and use of healthcare resources) is expected to increase worldwide due to the increasing prevalence of obesity and aging of the community [4]. Despite high prevalence and societal impact, OA’s etiology and pathogenesis remain elusive, which are impediments to developing effective preventative therapies and easing the condition’s symptoms. Although the etiology of OA is not fully understood, it is believed that a number of different environmental and genetic factors interact to cause its initiation and progression [5]. It is also recognized that OA is a heterogeneous group of diseases with different pathogenesis in different joints [6]. Age is the strongest risk factor for all joint OA, while obesity appears to confer the greatest risk of knee OA, particularly in women [7]. Twin studies suggest a strong genetic predisposition to hand and hip OA, with a heritability estimate of over 64 % [8, 9]. Genetic effects on knee OA are modest with a heritability of 39 % [8], but significant for knee OA progression, with a heritability of over 69 % [10]. This has led to vigorous effort and huge investment by the research community into identifying specific OA genes. Presently, there are at least 10 genome-wide association studies (GWAS) [11], resulting in 15 genetic loci that have achieved GWAS significance level [12]. It appears that these OA-associated genetic factors are joint specific and have only modest effects with an odds ratio of
