Heme Oxygenase-1 and Osteoarthritis: Comparison
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Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. 

  • heme oxygenase-1 (HO-1)
  • osteoarthritis

1. Introduction

Osteoarthritis (OA) is the most common joint disorder that mainly affects the knee joints and is linked to an increasing socioeconomic impact owing to an growing aging population [1]. Despite its prevalence, there are currently limited treatment options available for the prevention and slowing of disease progression. OA is a complex and multifaceted whole joint disease that is characterized by articular cartilage degradation with subchondral bone sclerosis and changes in the meniscus and ligaments [2,3]. The pathological process of OA is characterized by an imbalance between receding anabolic processes and accumulating catabolic processes in the joint. Various events, such as aging and joint injury, upregulate the production of pro-inflammatory agents of oxidative stress that contribute to this imbalance.

Osteoarthritis (OA) is the most common joint disorder that mainly affects the knee joints and is linked to an increasing socioeconomic impact owing to an growing aging population [1]. Despite its prevalence, there are currently limited treatment options available for the prevention and slowing of disease progression. OA is a complex and multifaceted whole joint disease that is characterized by articular cartilage degradation with subchondral bone sclerosis and changes in the meniscus and ligaments [2][3]. The pathological process of OA is characterized by an imbalance between receding anabolic processes and accumulating catabolic processes in the joint. Various events, such as aging and joint injury, upregulate the production of pro-inflammatory agents of oxidative stress that contribute to this imbalance.

Oxidative stress is established as a crucial factor driving age-associated diseases. The production of oxygen radicals, collectively known as reactive oxygen species (ROS), is elevated in various tissues including joint tissues with aging and diseases [4,5,6]. Oxidative stress-related imbalances between the production of ROS and the antioxidant capacity of joint cells such as chondrocytes and synovial fibroblasts has been identified as a major component of OA progression [5,7,8,9,10]. Contemporary studies, including those from our group, reported that genetically or chemically-induced antioxidant signals prevent cartilage degeneration and OA severity in aging and surgically-induced OA models [11,12,13,14,15]. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, is one of the most important antioxidant cytoprotective enzymes involved in the biological response to inflammation stimuli and oxidative stress. Protective functions of HO-1 were reported in numerous diseases, such as in neurodegeneration, rheumatoid arthritis (RA), and OA [10,16,17,18]. We also reported that constitutive expression of HO-1 in menisci and articular cartilage in mice reduce the severity of OA and intervertebral disc degeneration [13,19,20].

Oxidative stress is established as a crucial factor driving age-associated diseases. The production of oxygen radicals, collectively known as reactive oxygen species (ROS), is elevated in various tissues including joint tissues with aging and diseases [4][5][6]. Oxidative stress-related imbalances between the production of ROS and the antioxidant capacity of joint cells such as chondrocytes and synovial fibroblasts has been identified as a major component of OA progression [5][7][8][9][10]. Contemporary studies, including those from our group, reported that genetically or chemically-induced antioxidant signals prevent cartilage degeneration and OA severity in aging and surgically-induced OA models [11][12][13][14][15]. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, is one of the most important antioxidant cytoprotective enzymes involved in the biological response to inflammation stimuli and oxidative stress. Protective functions of HO-1 were reported in numerous diseases, such as in neurodegeneration, rheumatoid arthritis (RA), and OA [10][16][17][18]. We also reported that constitutive expression of HO-1 in menisci and articular cartilage in mice reduce the severity of OA and intervertebral disc degeneration [13][19][20].

HO-1 expression and enzymatic function are mostly regulated at the transcriptional level. The principal HO-1 transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) facilitates a highly potent cellular defense response against oxidative stress by promoting the transcription of an array of genes, including HO-1, that are widely involved in redox homeostasis, xenobiotic detoxification, and metabolism [18,21]. Running counter to Nrf2, the bric-a-brac, tramtrack, and broad complex (BTB), and “cap ‘n’ collar” (CNC) homologue 1 (Bach1) are widely expressed transcriptional repressors of HO-1 belonging to the basic region leucine zipper factor family (CNC-bZIP). Under normal conditions, Bach1 and small Maf proteins form heterodimers that inhibit the transcription of the aforementioned Nrf2-regulated genes [22]. Although the main function of HO-1 is the same in both humans and rodents, previous study indicates that the mechanisms regulating their expression differs. In particular, specificity protein 1 (Sp1) and CCCTC-binding factor (CTCF) are unique to human HO-1 expression regulation [23,24]. Gene expression experiments examining Nrf2 and Bach1 implicate a clear relationship between HO-1 and OA pathogenesis in mouse models [11,13]. In addition, Nrf2/HO-1-inducible drugs have been investigated for their therapeutic potential in OA by assessing their capacity to prevent cartilage degeneration in in vitro and in vivo animal models [14,25,26,27].

HO-1 expression and enzymatic function are mostly regulated at the transcriptional level. The principal HO-1 transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) facilitates a highly potent cellular defense response against oxidative stress by promoting the transcription of an array of genes, including HO-1, that are widely involved in redox homeostasis, xenobiotic detoxification, and metabolism [18][21]. Running counter to Nrf2, the bric-a-brac, tramtrack, and broad complex (BTB), and “cap ‘n’ collar” (CNC) homologue 1 (Bach1) are widely expressed transcriptional repressors of HO-1 belonging to the basic region leucine zipper factor family (CNC-bZIP). Under normal conditions, Bach1 and small Maf proteins form heterodimers that inhibit the transcription of the aforementioned Nrf2-regulated genes [22]. Although the main function of HO-1 is the same in both humans and rodents, previous study indicates that the mechanisms regulating their expression differs. In particular, specificity protein 1 (Sp1) and CCCTC-binding factor (CTCF) are unique to human HO-1 expression regulation [23][24]. Gene expression experiments examining Nrf2 and Bach1 implicate a clear relationship between HO-1 and OA pathogenesis in mouse models [11][13]. In addition, Nrf2/HO-1-inducible drugs have been investigated for their therapeutic potential in OA by assessing their capacity to prevent cartilage degeneration in in vitro and in vivo animal models [14][25][26][27].

2. Osteoarthritis Pathogenesis and Its Relationship with Oxidative Stress

2.1. Osteoarthritis Development

OA is the most common form of arthritis and is known to manifest in the knee, hip, and hand joints. The condition is frequently associated with functional limitation and physical disability among the elderly [2,28], that often has severe consequences on their quality of life. Cases of OA are often classified into either primary or secondary forms (see

OA is the most common form of arthritis and is known to manifest in the knee, hip, and hand joints. The condition is frequently associated with functional limitation and physical disability among the elderly [2][28], that often has severe consequences on their quality of life. Cases of OA are often classified into either primary or secondary forms (see

Table 1). Primary OA is an intrinsically occurring condition caused by the aging process that universally develops in a joint gradually over a 10–15-year period. Conversely, secondary OA is characterized by traumatic and abnormal inflammatory changes localized to an area of injury in the joint caused by extrinsic risk factors, such as trauma and obesity. Age is a key risk factor for the development of OA. OA treatment is currently limited to pain management by non-steroidal anti-inflammatory drugs (NSAIDs), surgical treatment, and physical therapy, because there are no clinically approved disease-modifying osteoarthritis drugs (DMOADs) currently available [29,30]. Understanding the pathological mechanisms of OA development is needed to develop agents for OA treatment. OA pathogenesis is characterized by an imbalance between dwindling anabolic and escalating catabolic processes in the joint. Mechanistically, metabolic imbalances that manifest during OA progression are driven by numerous factors, including disintegrin-like and metallopeptidase with a thrombospondin type 1 motif 5 (ADAMTS5), matrix metalloproteinase-13 (MMP-13), various pro-oxidant factors, and hedgehog signaling [5,31,32,33,34,35]. MMP-13 and ADAMTS5 are matrix-degradation enzymes that play essential roles in OA development; they are responsible for facilitating the degradation of major extracellular matrix (ECM) components such as type 2 collagen (COL2A1) and aggrecan (ACAN) in articular cartilage [31,32,33,36].

). Primary OA is an intrinsically occurring condition caused by the aging process that universally develops in a joint gradually over a 10–15-year period. Conversely, secondary OA is characterized by traumatic and abnormal inflammatory changes localized to an area of injury in the joint caused by extrinsic risk factors, such as trauma and obesity. Age is a key risk factor for the development of OA. OA treatment is currently limited to pain management by non-steroidal anti-inflammatory drugs (NSAIDs), surgical treatment, and physical therapy, because there are no clinically approved disease-modifying osteoarthritis drugs (DMOADs) currently available [29][30]. Understanding the pathological mechanisms of OA development is needed to develop agents for OA treatment. OA pathogenesis is characterized by an imbalance between dwindling anabolic and escalating catabolic processes in the joint. Mechanistically, metabolic imbalances that manifest during OA progression are driven by numerous factors, including disintegrin-like and metallopeptidase with a thrombospondin type 1 motif 5 (ADAMTS5), matrix metalloproteinase-13 (MMP-13), various pro-oxidant factors, and hedgehog signaling [5][31][32][33][34][35]. MMP-13 and ADAMTS5 are matrix-degradation enzymes that play essential roles in OA development; they are responsible for facilitating the degradation of major extracellular matrix (ECM) components such as type 2 collagen (COL2A1) and aggrecan (ACAN) in articular cartilage [31][32][33][36].

Table 1.

Causes of osteoarthritis (OA) pathogenesis in human patients.

Risk Factor Primary or Secondary Mechanism
Aging Primary cellular senescence, mitochondrial dysfunction
Genetics Primary GDF5, DVWA etc, See (review [43])GDF5, DVWA etc, See (review [37])
Obesity Secondary mechanical stress, inflammatory mediators
Trauma Secondary joint instability, pro-inflammation
Overuse Secondary wear and tear, pro-inflammation
Varus and valgus alignment Secondary chronic overload, wear and tear
Different mechanisms contribute to OA pathogenesis such as reduced self-renewal ability, increased production of pro-inflammatory mediators, and oxidative stress. Inflammation and oxidative stress are recognized as important risk factors in both primary and secondary OA. The inflammatory cytokines interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2) are mediators of inflammatory states and cartilage degradation in both RA and OA [37]. In particular, IL-1β and TNF-α activate chondrocytes to produce MMP-13 and ADAMTS5 and promote catabolic conditions [38,39]. Previous studies demonstrated that IL-1β activates mitogen-activated protein kinase (MAPK) signaling pathways such as extracellular signal-regulated kinase (ERK), p38, and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathways in human articular chondrocytes [40,41,42]. These signaling pathways are well-known local and systemic activators of the inflammatory state and are therefore potent promoters of pathogenesis.

Different mechanisms contribute to OA pathogenesis such as reduced self-renewal ability, increased production of pro-inflammatory mediators, and oxidative stress. Inflammation and oxidative stress are recognized as important risk factors in both primary and secondary OA. The inflammatory cytokines interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2) are mediators of inflammatory states and cartilage degradation in both RA and OA [38]. In particular, IL-1β and TNF-α activate chondrocytes to produce MMP-13 and ADAMTS5 and promote catabolic conditions [39][40]. Previous studies demonstrated that IL-1β activates mitogen-activated protein kinase (MAPK) signaling pathways such as extracellular signal-regulated kinase (ERK), p38, and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathways in human articular chondrocytes [41][42][43]. These signaling pathways are well-known local and systemic activators of the inflammatory state and are therefore potent promoters of pathogenesis.

2.2. Oxidative Stress and Antioxidant Signaling in Joints

ROS are free radicals derived from molecular oxygen. Examples of ROS include hydroxyl radicals, hydrogen peroxide (H

2

O

2), superoxide anions, nitric oxide (NO), and hypochlorite ions. Under normal conditions, ROS are generated by a number of typical cell functional process (such as ATP synthesis in the mitochondria) and serve as important cellular messengers and mediators of immune responses during bacterial infection [44,45]. The overaccumulation of ROS is referred to as a state of oxidative stress. In the joint, oxidative stress is induced by aging, mechanical stress, and inflammation. In OA, oxidative stress has also been associated with abnormal chondrocyte death, cellular senescence, and the expression of catabolic factors such as inflammatory cytokines and ECM-degrading proteases [46,47,48,49,50]. Accumulations of ROS activate the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome in synovial membrane macrophages and increases the expression of pro-inflammatory cytokines IL-18 and IL-1β [51]. These pro-inflammatory cytokines stimulate chondrocytes and osteoclasts to activate cartilage degradation pathways, thereby driving OA pathogenesis.

), superoxide anions, nitric oxide (NO), and hypochlorite ions. Under normal conditions, ROS are generated by a number of typical cell functional process (such as ATP synthesis in the mitochondria) and serve as important cellular messengers and mediators of immune responses during bacterial infection [44][45]. The overaccumulation of ROS is referred to as a state of oxidative stress. In the joint, oxidative stress is induced by aging, mechanical stress, and inflammation. In OA, oxidative stress has also been associated with abnormal chondrocyte death, cellular senescence, and the expression of catabolic factors such as inflammatory cytokines and ECM-degrading proteases [46][47][48][49][50]. Accumulations of ROS activate the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome in synovial membrane macrophages and increases the expression of pro-inflammatory cytokines IL-18 and IL-1β [51]. These pro-inflammatory cytokines stimulate chondrocytes and osteoclasts to activate cartilage degradation pathways, thereby driving OA pathogenesis.

Because ROS production and activity play a pivotal role in the maintenance of cellular homeostasis, mammalian cells have acquired adaptive protective mechanisms that regulate the accumulation of ROS through the production of antioxidant factors. These mechanisms have an immense influence on intracellular signaling, with studies indicating that joint cells are highly sensitive to the loss of these regulatory and control systems during OA development [12,52]. Genetic modification studies of antioxidant genes such as superoxide dismutase 2 (SOD2) and HO-1 showed that the dysregulation of antioxidative mechanisms enhances cartilage degradation, synovial inflammation, and chondrocyte senescence [6,12,53,54,55]. Moreover, Nrf2-deficiency augments cartilage injuries and oxidative damage in adjuvant-induced RA joints [56,57]. The role of Nrf2 in RA is summarized and further detailed in several other reviews [10,58]. On the other hand, Nrf2 activation and HO-1 expression using a histone deacetylase inhibitor trichostatin A (TSA) represses IL-1β-induced MMP gene expression in chondrocytes. Nrf2 acetylation is an important upstream regulatory mechanism for Nrf2 transcriptional activation [59,60]. Similarly, in vivo TSA treatment has been reported to decrease OA severity and reduce MMP expression in mice while increasing HO-1 [11]. Although HO-1 expression in knee cartilage is known to decrease with aging, our previous study using Bach1-deficient mice demonstrated that the consecutive induction of HO-1 in chondrocytes can prevent OA development in both aging and surgically-induced preclinical mouse models [13,19]. A number of reports have noted that inducers of antioxidant signals such as N-acetyl cysteine (NAC), S-allyl cysteine, and procyanidins are able to attenuate OA development induced by joint instability in mice models [61,62,63].

Because ROS production and activity play a pivotal role in the maintenance of cellular homeostasis, mammalian cells have acquired adaptive protective mechanisms that regulate the accumulation of ROS through the production of antioxidant factors. These mechanisms have an immense influence on intracellular signaling, with studies indicating that joint cells are highly sensitive to the loss of these regulatory and control systems during OA development [12][52]. Genetic modification studies of antioxidant genes such as superoxide dismutase 2 (SOD2) and HO-1 showed that the dysregulation of antioxidative mechanisms enhances cartilage degradation, synovial inflammation, and chondrocyte senescence [6][12][53][54][55]. Moreover, Nrf2-deficiency augments cartilage injuries and oxidative damage in adjuvant-induced RA joints [56][57]. The role of Nrf2 in RA is summarized and further detailed in several other reviews [10][58]. On the other hand, Nrf2 activation and HO-1 expression using a histone deacetylase inhibitor trichostatin A (TSA) represses IL-1β-induced MMP gene expression in chondrocytes. Nrf2 acetylation is an important upstream regulatory mechanism for Nrf2 transcriptional activation [59][60]. Similarly, in vivo TSA treatment has been reported to decrease OA severity and reduce MMP expression in mice while increasing HO-1 [11]. Although HO-1 expression in knee cartilage is known to decrease with aging, our previous study using Bach1-deficient mice demonstrated that the consecutive induction of HO-1 in chondrocytes can prevent OA development in both aging and surgically-induced preclinical mouse models [13][19]. A number of reports have noted that inducers of antioxidant signals such as N-acetyl cysteine (NAC), S-allyl cysteine, and procyanidins are able to attenuate OA development induced by joint instability in mice models [61][62][63].

Collectively, these studies indicate that the imbalances in redox homeostasis caused by oxidative stress can be corrected by the appropriate application of the induction of antioxidant signals. Therefore, pharmacological modulation of antioxidant signals may represent a novel and promising strategy for the prevention of OA.

3. The Role of Heme Oxygenase-1 in Arthritis

3.1. Properties of Heme Oxygenase-1

Heme oxygenase-1 (HO-1) is a rate-limiting cytoprotective enzyme encoded by the

HMOX1

gene that functions to degrade free heme into equimolar amounts of ferrous iron (Fe

2+), carbon monoxide (CO), and biliverdin (which is later converted into bilirubin by biliverdin reductase) [64,65,66]. It is a ubiquitously expressed [67] member of the heat shock protein family and is one of two active isozymes that make up the HO system. In contrast to its variant isozyme HO-2 (encoded by the

), carbon monoxide (CO), and biliverdin (which is later converted into bilirubin by biliverdin reductase) [64][65][66]. It is a ubiquitously expressed [67] member of the heat shock protein family and is one of two active isozymes that make up the HO system. In contrast to its variant isozyme HO-2 (encoded by the

HMOX2

gene), HO-1 expression is inducible, whereas HO-2 is constitutively expressed and not inducible. A catalytically inactive third isoform of HO, HO-3, has also been described. HO-3 shares ~90% of its amino acid sequence identity with HO-2 [68]. Structurally, human HO-1 has a molecular weight of ~32 kDa containing 288 amino acid residues and shares a high level of sequence similarity with rodents. HO-1 is a single compact domain consisting of mostly alpha helical folds. These folds are responsible for aiding substrate orientation within the heme pocket and C-terminal, an essential domain for facilitating anchorage to the smooth endoplasmic reticulum [69].

3.2. Anti-Inflammatory Function of Heme Oxygenase-1

HO-1 has been shown to possess many important immunomodulatory and anti-inflammatory functions. The latest insights into the immunomodulatory functions of HO-1 have been the subject of several reviews [70,71]. A significant component of the interactions between HO-1 and the immune response is defined by its relationship with macrophages. Macrophages are an essential cellular component of the immunomodulatory system and the subsequent inflammatory response. Macrophages adopt different functional programs in response to signals from their microenvironment: they are often classified as having either a pro-inflammatory M1 (classically activated) or anti-inflammatory M2 (alternatively activated) phenotype [72]. Impairment of the balance between M1 and M2 macrophage polarization is thought to be the cause of several inflammatory-related diseases, including arthritis [72]. HO-1 expression in macrophages is dependent on stimulation by multiple transcriptional signals and cytokines. HO-1 induction was observed to direct macrophage polarization towards an M2 phenotype, thereby exerting an anti-inflammatory response [73]. Vitali et al. showed that HO-1-deficient mice-derived macrophages are more sensitive to hypoxia-induced oxidative stress, which was characterized by increased NLRP3 inflammasome signaling [70]. The elevation of HO-1 conversely attenuated complement-dependent inflammation, whereas its inhibition led to a potentiation of the inflammatory response [74]. Significantly, living and autopsy case studies have shown that HO-1-deficient mice exhibit a similar phenotype to genetically HO-1-deficient humans, such as growth retardation, anemia, iron deposition, and vulnerability to stressful injury [75,76]. In contrast, constitutively expressed HO-2-deficient mice retain an intact immune system [77]. These results indicate that inducible HO-1 carries out crucial cytoprotective functions through its immunomodulatory activities.

HO-1 has been shown to possess many important immunomodulatory and anti-inflammatory functions. The latest insights into the immunomodulatory functions of HO-1 have been the subject of several reviews [70][71]. A significant component of the interactions between HO-1 and the immune response is defined by its relationship with macrophages. Macrophages are an essential cellular component of the immunomodulatory system and the subsequent inflammatory response. Macrophages adopt different functional programs in response to signals from their microenvironment: they are often classified as having either a pro-inflammatory M1 (classically activated) or anti-inflammatory M2 (alternatively activated) phenotype [72]. Impairment of the balance between M1 and M2 macrophage polarization is thought to be the cause of several inflammatory-related diseases, including arthritis [72]. HO-1 expression in macrophages is dependent on stimulation by multiple transcriptional signals and cytokines. HO-1 induction was observed to direct macrophage polarization towards an M2 phenotype, thereby exerting an anti-inflammatory response [73]. Vitali et al. showed that HO-1-deficient mice-derived macrophages are more sensitive to hypoxia-induced oxidative stress, which was characterized by increased NLRP3 inflammasome signaling [70]. The elevation of HO-1 conversely attenuated complement-dependent inflammation, whereas its inhibition led to a potentiation of the inflammatory response [74]. Significantly, living and autopsy case studies have shown that HO-1-deficient mice exhibit a similar phenotype to genetically HO-1-deficient humans, such as growth retardation, anemia, iron deposition, and vulnerability to stressful injury [75][76]. In contrast, constitutively expressed HO-2-deficient mice retain an intact immune system [77]. These results indicate that inducible HO-1 carries out crucial cytoprotective functions through its immunomodulatory activities.

3.3. Regulation of Heme Oxygenase-1

HMOX1 is mostly regulated at the transcriptional level, with the regulatory mechanisms underlying its expression being highly complex and often cell-specific due to the extremely diverse array of stimuli that are able to induce HO-1. For example, HO-1 induction by heme, heavy metals, growth factors, NO, oxidized lipids, and cytokines has been experimentally tested and verified [78,79]. In particular, a large number of studies have reported that the expression of HO-1 is induced by stimuli that increase intracellular levels of ROS, such as heme, heavy metals, UV light, hydrogen peroxide, and lipopolysaccharide, or by stimuli that deplete cellular glutathione stores, including buthionine sulfoximine, sodium arsenite, and iodo-acetamide [80]. The linkage of HO-1-inducible expression to oxidative stress stimuli indicates that it is a component of an adaptive cytoprotective response to environmental stressors. Furthermore, it has been shown that scavengers of ROS, such as NAC, inhibit or reduce the extent of HO-1 induction by oxidative stress [81]. These results indicate that intracellular ROS plays an important role in

is mostly regulated at the transcriptional level, with the regulatory mechanisms underlying its expression being highly complex and often cell-specific due to the extremely diverse array of stimuli that are able to induce HO-1. For example, HO-1 induction by heme, heavy metals, growth factors, NO, oxidized lipids, and cytokines has been experimentally tested and verified [78][79]. In particular, a large number of studies have reported that the expression of HO-1 is induced by stimuli that increase intracellular levels of ROS, such as heme, heavy metals, UV light, hydrogen peroxide, and lipopolysaccharide, or by stimuli that deplete cellular glutathione stores, including buthionine sulfoximine, sodium arsenite, and iodo-acetamide [80]. The linkage of HO-1-inducible expression to oxidative stress stimuli indicates that it is a component of an adaptive cytoprotective response to environmental stressors. Furthermore, it has been shown that scavengers of ROS, such as NAC, inhibit or reduce the extent of HO-1 induction by oxidative stress [81]. These results indicate that intracellular ROS plays an important role in

HMOX1

gene expression regulation: free heme produced in response to oxidative stress is catabolized into a non-cytotoxic catabolite because oxidative stress is coupled to the induction of HO-1 [82].

3.3.1. Transcriptional Regulation

HMOX1 transcription can be induced by various signal transduction pathways that activate different transcription factors [58,83]. Given that the induction of HO-1 is tied to extracellular stimuli, its upstream mitogen-activated protein kinase (MAPK) signaling cascades such as ERK, c-Jun terminal kinase (JNK), and p38 MAPK are known to play a significant role in mediating gene expression [83,84,85,86,87]. However, the molecular regulation of HO-1 induction by stimuli is different between human and rodents [88]. Previous studies using an in vitro and humanized HO-1 transgenic mouse model revealed that several transcriptional factors such as transcription factor jun-B (JunB), Sp1, upstream stimulatory factor (USF) 1/2, and CTCF are uniquely involved in human HO-1 induction mechanisms through chromatin loop formation [23,24].

transcription can be induced by various signal transduction pathways that activate different transcription factors [58][83]. Given that the induction of HO-1 is tied to extracellular stimuli, its upstream mitogen-activated protein kinase (MAPK) signaling cascades such as ERK, c-Jun terminal kinase (JNK), and p38 MAPK are known to play a significant role in mediating gene expression [83][84][85][86][87]. However, the molecular regulation of HO-1 induction by stimuli is different between human and rodents [88]. Previous studies using an in vitro and humanized HO-1 transgenic mouse model revealed that several transcriptional factors such as transcription factor jun-B (JunB), Sp1, upstream stimulatory factor (USF) 1/2, and CTCF are uniquely involved in human HO-1 induction mechanisms through chromatin loop formation [23][24].

Nrf2, a 66 kDa protein and a member of the CNC-bZIP family of transcription factors, is considered to be particularly important given its crucial role for the protection of joint destruction through facilitating the induction of target genes such as NAD(P)H:quinone oxidoreductase 1 (NQO1), and, significantly, HO-1 [10,18,21,89,90]. The activity of Nrf2 is functional in a wide-ranging metabolic response to oxidative stress and constitutes a cellular sensor for oxidative stress by a nuclear shuttling mechanism with the cytosolic regulator protein Kelch-like ECH-associated protein 1 (Keap1) [91,92,93]. Kruppel-like factor 2 (KLF2), a member of the zinc finger family, has emerged as an important transcription factor in the development of OA. KLF2 expression is reduced in OA patient-derived cartilage and in IL-1β-stimulated SW1353 human chondrocytes. Genetic and pharmacological overexpression of KLF2 protects against OA progression by increasing the expression of HO-1 and NQO1 through the enhancement of Nrf2 nuclear translocation [94]. Previous studies reported that increasing KLF2 levels reduced the expression of MMP-3 and MMP-13 in monocytes, which attenuates the cartilage degradation process associated with OA [95]. Moreover, in human endothelial cells, KLF2 has been shown to play a crucial role in protecting against oxidative damage through the activation of Nrf2/HO-1 signaling [96,97].

Nrf2, a 66 kDa protein and a member of the CNC-bZIP family of transcription factors, is considered to be particularly important given its crucial role for the protection of joint destruction through facilitating the induction of target genes such as NAD(P)H:quinone oxidoreductase 1 (NQO1), and, significantly, HO-1 [10][18][21][89][90]. The activity of Nrf2 is functional in a wide-ranging metabolic response to oxidative stress and constitutes a cellular sensor for oxidative stress by a nuclear shuttling mechanism with the cytosolic regulator protein Kelch-like ECH-associated protein 1 (Keap1) [91][92][93]. Kruppel-like factor 2 (KLF2), a member of the zinc finger family, has emerged as an important transcription factor in the development of OA. KLF2 expression is reduced in OA patient-derived cartilage and in IL-1β-stimulated SW1353 human chondrocytes. Genetic and pharmacological overexpression of KLF2 protects against OA progression by increasing the expression of HO-1 and NQO1 through the enhancement of Nrf2 nuclear translocation [94]. Previous studies reported that increasing KLF2 levels reduced the expression of MMP-3 and MMP-13 in monocytes, which attenuates the cartilage degradation process associated with OA [95]. Moreover, in human endothelial cells, KLF2 has been shown to play a crucial role in protecting against oxidative damage through the activation of Nrf2/HO-1 signaling [96][97].

The heme-binding protein Bach1 is a transcriptional repressor of

HMOX1

due to its competitive relationship with Nrf2 for binding to ARE [98]. During oxidative stress or increasing heme concentrations, Bach1 is displaced from ARE and exported out of the nucleus to be degraded so that Nrf2 can associate with Maf and bind to ARE sequences [98]. Thus, cellular HO-1 inducive mechanisms are tightly regulated by extracellular conditions through the described Nrf2/Keap1/Bach1 system.

3.3.2. MicroRNA-Mediated Post-Transcriptional Regulation

MicroRNAs (miRNAs) are a major class of small noncoding RNAs found in animals, plants, and some viruses, which function as negative regulators of gene expression. They suppress messenger RNA (mRNA) translation by promoting their degradation via the RNA-induced silencing complex (RISC) [99,100]. miRNA expression levels are frequently altered by aging-related disorders such as OA and cancer [101,102,103,104,105]. miRNAs exist that indirectly modulate HO-1 upstream regulatory factors, such as Bach1, Nrf2, and Keap1. Eades et al. demonstrated, using miRNA-based microarray analysis, that miR-200a expression is silenced in breast cancer cells, and that ectopic re-expression increases Nrf2 nuclear translocation by directly binding to the Keap1 mRNA 3′-untranslated region (3′-UTR) and facilitating its degradation [106]. Kim et al. found that hypoxia-inducible miR-101 induces HO-1 expression in endothelial cells. Upregulated miR-101 targets the E3 ubiquitin ligase Cullin3 and stabilizes Nrf2, resulting in the enhancement of Nrf2 translocation into the nucleus [107]. On the other hand, ectopic expression of miR-28 in mammalian endothelial cells directly downregulates Nrf2 protein expression via 3′-UTR binding of Nrf2 mRNA independently from the Keap1 pathway [108]. Sangokoya et al. identified that patients of sickle cell disease highly express miR-144 in erythrocytes and abrogate antioxidant signals. miR-144 regulates Nrf2 expression through binding to the 3′-UTR of Nrf2 mRNA and modulates the oxidative stress response in K562 and primary erythroid progenitor cells [109].

MicroRNAs (miRNAs) are a major class of small noncoding RNAs found in animals, plants, and some viruses, which function as negative regulators of gene expression. They suppress messenger RNA (mRNA) translation by promoting their degradation via the RNA-induced silencing complex (RISC) [99][100]. miRNA expression levels are frequently altered by aging-related disorders such as OA and cancer [101][102][103][104][105]. miRNAs exist that indirectly modulate HO-1 upstream regulatory factors, such as Bach1, Nrf2, and Keap1. Eades et al. demonstrated, using miRNA-based microarray analysis, that miR-200a expression is silenced in breast cancer cells, and that ectopic re-expression increases Nrf2 nuclear translocation by directly binding to the Keap1 mRNA 3′-untranslated region (3′-UTR) and facilitating its degradation [106]. Kim et al. found that hypoxia-inducible miR-101 induces HO-1 expression in endothelial cells. Upregulated miR-101 targets the E3 ubiquitin ligase Cullin3 and stabilizes Nrf2, resulting in the enhancement of Nrf2 translocation into the nucleus [107]. On the other hand, ectopic expression of miR-28 in mammalian endothelial cells directly downregulates Nrf2 protein expression via 3′-UTR binding of Nrf2 mRNA independently from the Keap1 pathway [108]. Sangokoya et al. identified that patients of sickle cell disease highly express miR-144 in erythrocytes and abrogate antioxidant signals. miR-144 regulates Nrf2 expression through binding to the 3′-UTR of Nrf2 mRNA and modulates the oxidative stress response in K562 and primary erythroid progenitor cells [109].

miRNAs also modulate HO-1 activity by directly regulating

HMOX1

expression. Beckman et al. performed in silico analysis of the human

HMOX1

-3′ UTR and identified two candidate miRNAs, miR-377 and miR-217, as possible inhibitors of

HMOX1

. Subsequent experiments found that co-transfection of miR-377 and miR-217 downregulated the luciferase activity of

HMOX1

-3′ UTR and HO-1 protein expression levels [110]. Our previous study established that miR-140 regulates HO-1 expression by binding to the 3′-UTR of

BACH1

in human primary chondrocytes [14]. Similar investigations reported that miR-155 and miR-196a regulates the expression of HO-1 through the reduction in

BACH1 expression in endothelial cells or hepatoma cells [111,112]. miR-155 is a pro-inflammatory miRNA that is significantly upregulated in OA and RA joints [113,114,115,116]. Moreover, upregulated miR-155 inhibits the expression of a number of core proteins in the autophagy cascade and promotes the cartilage degradation pathway in chondrocytes [113]. Autophagy is a critical evolutionarily conserved eukaryotic process that functions to maintain cellular homeostasis in response to changes to the environment, including in chondrocyte protection [117,118]. While autophagic activity is decreased in aging and OA-induced mouse knee cartilage, HO-1 overexpression is able to rescue the suppression of autophagic activity [13,50]. The pro-inflammatory cytokine TNF-α induces the expression of HO-1 and miR-155 in endothelial cells [111]. In contrast, IL-1β stimuli downregulates the expression of HO-1 and miR-140 in articular chondrocytes [14]. miR-140 is highly expressed in normal cartilage but is significantly reduced in OA cartilage. miR-140 is a cartilage-specific miRNA and is the most important regulatory factor in cartilage homeostasis [102,103]. Previously, we found that carnosic acid (CA), a natural flavonoid, raises the expression of HO-1 and miR-140 in articular chondrocytes through the transcriptional downregulation of

expression in endothelial cells or hepatoma cells [111][112]. miR-155 is a pro-inflammatory miRNA that is significantly upregulated in OA and RA joints [113][114][115][116]. Moreover, upregulated miR-155 inhibits the expression of a number of core proteins in the autophagy cascade and promotes the cartilage degradation pathway in chondrocytes [113]. Autophagy is a critical evolutionarily conserved eukaryotic process that functions to maintain cellular homeostasis in response to changes to the environment, including in chondrocyte protection [117][118]. While autophagic activity is decreased in aging and OA-induced mouse knee cartilage, HO-1 overexpression is able to rescue the suppression of autophagic activity [13][50]. The pro-inflammatory cytokine TNF-α induces the expression of HO-1 and miR-155 in endothelial cells [111]. In contrast, IL-1β stimuli downregulates the expression of HO-1 and miR-140 in articular chondrocytes [14]. miR-140 is highly expressed in normal cartilage but is significantly reduced in OA cartilage. miR-140 is a cartilage-specific miRNA and is the most important regulatory factor in cartilage homeostasis [102][103]. Previously, we found that carnosic acid (CA), a natural flavonoid, raises the expression of HO-1 and miR-140 in articular chondrocytes through the transcriptional downregulation of

BACH1

. In addition, we observed that CA treatment alleviates IL-1β-induced cartilage damage. These results suggest that the regulation of Bach1-mediated HO-1 expression by miRNA may depend on cell type and context.

3.4. Heme Oxygenase-1 in Osteoarthritis

Elevation of oxidative stress in joint tissue has long been established as a crucial factor mediating the articular cartilage degradation process during OA [5,119]. Given its antioxidant properties, several studies have suggested a protective role of HO-1 in OA pathogenesis. It has been reported that HO-1 is significantly upregulated in human and mouse models of OA, with higher levels of expression being observed in areas of cartilage damage [120,121]. However, discrepancies exist regarding Nrf2/HO-1 expression between OA cartilage and IL-1β-induced OA-like chondrocytes [122,123]. Our previous study showed that HO-1 protein expression levels in IL-1β-primed normal human primary chondrocytes are significantly decreased compared with a control [14]. Further investigation is required to determine if there is a relationship between Nrf2/HO-1 signaling and OA.

Elevation of oxidative stress in joint tissue has long been established as a crucial factor mediating the articular cartilage degradation process during OA [5][119]. Given its antioxidant properties, several studies have suggested a protective role of HO-1 in OA pathogenesis. It has been reported that HO-1 is significantly upregulated in human and mouse models of OA, with higher levels of expression being observed in areas of cartilage damage [120][121]. However, discrepancies exist regarding Nrf2/HO-1 expression between OA cartilage and IL-1β-induced OA-like chondrocytes [122][123]. Our previous study showed that HO-1 protein expression levels in IL-1β-primed normal human primary chondrocytes are significantly decreased compared with a control [14]. Further investigation is required to determine if there is a relationship between Nrf2/HO-1 signaling and OA.

HO-1 is able to confer a protective effect in OA chondrocytes by inhibiting the pro-catabolic effects of IL-1β on the ECM components MMP-1 and MMP-13 [124,125] while reducing the production of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-18 [126]. Conversely, HO-1 simultaneously enhances the synthesis of anabolic factors such as IGF-1, proteoglycan, and COL2A1 [127], and increases anti-inflammatory IL-10 levels [124]. A wide array of studies has investigated the protective effects of HO-1 in OA chondrocytes through its regulatory relationship with the Nrf2/Bach1 system. Nrf2 activation in OA chondrocytes has been reported to inhibit mitochondrial dysfunction, ROS production, and apoptosis induced by IL-1β [120]. Nrf2 activity also inhibits inflammation and ECM degradation in OA chondrocytes [51,94,128] and regulates cellular differentiation in chondrocytes [129,130]. Bach1 deficiency significantly elevates HO-1 expression in healthy and aged articular cartilage and reduces the severity of age-related OA-like changes [13]. Moreover, Bach1 deficiency significantly inhibits the severity of OA-like changes, such as meniscus degradation, inflammatory changes in synovium, osteophyte formation, and subchondral bone thickening [13,19]. All in all, these results suggest that HO-1 expressed in whole joint cells plays a critical role in the maintenance of joint homeostasis.

HO-1 is able to confer a protective effect in OA chondrocytes by inhibiting the pro-catabolic effects of IL-1β on the ECM components MMP-1 and MMP-13 [124][125] while reducing the production of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-18 [126]. Conversely, HO-1 simultaneously enhances the synthesis of anabolic factors such as IGF-1, proteoglycan, and COL2A1 [127], and increases anti-inflammatory IL-10 levels [124]. A wide array of studies has investigated the protective effects of HO-1 in OA chondrocytes through its regulatory relationship with the Nrf2/Bach1 system. Nrf2 activation in OA chondrocytes has been reported to inhibit mitochondrial dysfunction, ROS production, and apoptosis induced by IL-1β [120]. Nrf2 activity also inhibits inflammation and ECM degradation in OA chondrocytes [51][94][128] and regulates cellular differentiation in chondrocytes [129][130]. Bach1 deficiency significantly elevates HO-1 expression in healthy and aged articular cartilage and reduces the severity of age-related OA-like changes [13]. Moreover, Bach1 deficiency significantly inhibits the severity of OA-like changes, such as meniscus degradation, inflammatory changes in synovium, osteophyte formation, and subchondral bone thickening [13][19]. All in all, these results suggest that HO-1 expressed in whole joint cells plays a critical role in the maintenance of joint homeostasis.

3.5. Heme Oxygenase-1 and Osteoarthritis-Associated Cellular Senescence

Cellular senescence is a major instigator of both aging-associated and post-traumatic OA pathogenesis [131,132]. In particular, aging-induced cellular senescence is known to be the most important risk factor for primary OA progression. As such, senolytic drugs have rapidly captured the interest of academic research and business venture as a potential avenue for attenuating OA pathogenesis and pathology [133]. Senescent cells secrete a robust pro-inflammatory secretome, known as a senescence-associated secretory phenotype (SASP). A SASP consists of a variety of cytokines, growth factors, and other soluble and insoluble material that continuously alters the structure and function of surrounding cells and tissues in a paracrine manner [134]. Joint tissues (comprising articular cartilage, subchondral bone, synovium, and infrapatellar fat pad) suffering from OA induced by aging or trauma are likely to harbor senescent cells that secrete an OA-propagating SASP [134]. In addition, although the mechanism of action is not fully understood, it is known that oxidative stress induces senescence in chondrocytes through multiple complex signaling pathways [135]. ROS can further propagate this effect by eroding protective telomeres, resulting in accelerated senescence and chondrocyte apoptosis. Several studies have shown that high shear stress alone can induce chondrocyte senescence [136,137,138].

Cellular senescence is a major instigator of both aging-associated and post-traumatic OA pathogenesis [131][132]. In particular, aging-induced cellular senescence is known to be the most important risk factor for primary OA progression. As such, senolytic drugs have rapidly captured the interest of academic research and business venture as a potential avenue for attenuating OA pathogenesis and pathology [133]. Senescent cells secrete a robust pro-inflammatory secretome, known as a senescence-associated secretory phenotype (SASP). A SASP consists of a variety of cytokines, growth factors, and other soluble and insoluble material that continuously alters the structure and function of surrounding cells and tissues in a paracrine manner [134]. Joint tissues (comprising articular cartilage, subchondral bone, synovium, and infrapatellar fat pad) suffering from OA induced by aging or trauma are likely to harbor senescent cells that secrete an OA-propagating SASP [134]. In addition, although the mechanism of action is not fully understood, it is known that oxidative stress induces senescence in chondrocytes through multiple complex signaling pathways [135]. ROS can further propagate this effect by eroding protective telomeres, resulting in accelerated senescence and chondrocyte apoptosis. Several studies have shown that high shear stress alone can induce chondrocyte senescence [136][137][138].

Although still a largely unexplored avenue, a few studies have investigated the interplay between HO-1 induction and chondrocyte senescence. Principally, HO-1 has been documented to protect articular cartilage against cellular senescence. One study reported that cilostazol-induced senescence significantly attenuated HO-1 expression in human chondrocytes and, conversely, that HO-1 overexpression exerts a protective effect against cilostazol-induced senescence [53]. A follow-up study found that a regulator of HO-1 in stress-induced chondrocytes known as protein kinase casein kinase 2 (CK2) is associated with senescence in primary articular chondrocytes, and that the downregulation of CK2 induces cellular senescence by inhibiting the expression of HO-1 [139]. A separate investigation demonstrated that the expression of senescence markers such as senescence-associated β-galactosidase, p21, and caveolin1 were significantly decreased after HO-1 induction [53,140]. Taken together, while the mechanism by which HO-1 can suppress cellular senescence progression remains to be fully understood, these studies indicate that HO-1 may be a potential therapeutic target for aging-related OA development.

Although still a largely unexplored avenue, a few studies have investigated the interplay between HO-1 induction and chondrocyte senescence. Principally, HO-1 has been documented to protect articular cartilage against cellular senescence. One study reported that cilostazol-induced senescence significantly attenuated HO-1 expression in human chondrocytes and, conversely, that HO-1 overexpression exerts a protective effect against cilostazol-induced senescence [53]. A follow-up study found that a regulator of HO-1 in stress-induced chondrocytes known as protein kinase casein kinase 2 (CK2) is associated with senescence in primary articular chondrocytes, and that the downregulation of CK2 induces cellular senescence by inhibiting the expression of HO-1 [139]. A separate investigation demonstrated that the expression of senescence markers such as senescence-associated β-galactosidase, p21, and caveolin1 were significantly decreased after HO-1 induction [53][140]. Taken together, while the mechanism by which HO-1 can suppress cellular senescence progression remains to be fully understood, these studies indicate that HO-1 may be a potential therapeutic target for aging-related OA development.

 
 

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