Osteoarthritis (OA) is one of the most common joint diseases and is characterized by excessive degeneration of extracellular matrix components in the articular cartilage. The extracellular matrix of cartilage is composed mainly of the hyaluronan (HA)-aggrecan (a major cartilage proteoglycan) networks and the collagen fibrils of types II and XI collagens. The initial pathologic change of the articular cartilage in OA patients is the depletion of HA-aggrecan networks, which is followed by the degradation of collagen fibrils.
1Aggrecanases and cartilage matrix degradation.
, 2Okada Y: Proteinases and matrix degradation. Kelley and Firestein’s Textbook of Rheumatology, ed 10. Edited by Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Philadelphia: Elsevier Inc, 2017. pp. 106–125
Degradation of fibrillary collagens is ascribed to the proteinase actions of the matrix metalloproteinase family members with collagenolytic activity, such as matrix metalloproteinases 1, 13, and 14, and aggrecan appears to be degraded mainly by a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5, also called aggrecanases 1 and 2, respectively.
2Okada Y: Proteinases and matrix degradation. Kelley and Firestein’s Textbook of Rheumatology, ed 10. Edited by Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Philadelphia: Elsevier Inc, 2017. pp. 106–125
, 3Drug insight: aggrecanases as therapeutic targets for osteoarthritis.
, 4- Shiomi T.
- Lemaitre V.
- D'Armiento J.
- Okada Y.
Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases.
Overexpression of these matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 by chondrocytes in OA cartilage has been reported,
5- Imai K.
- Ohta S.
- Matsumoto T.
- Fujimoto N.
- Sato H.
- Seiki M.
- Okada Y.
Expression of membrane-type 1 matrix metalloproteinase and activation of progelatinase A in human osteoarthritic cartilage.
, 6- Shlopov B.V.
- Lie W.R.
- Mainardi C.L.
- Cole A.A.
- Chubinskaya S.
- Hasty K.A.
Osteoarthritic lesions: involvement of three different collagenases.
, 7- Bau B.
- Gebhard P.M.
- Haag J.
- Knorr T.
- Bartnik E.
- Aigner T.
Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro.
, 8- Naito S.
- Shiomi T.
- Okada A.
- Kimura T.
- Chijiiwa M.
- Fujita Y.
- Yatabe T.
- Komiya K.
- Enomoto H.
- Fujikawa K.
- Okada Y.
Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage.
and they are suggested to play a central role in collagen and aggrecan degradation in OA cartilage.
1Aggrecanases and cartilage matrix degradation.
, 2Okada Y: Proteinases and matrix degradation. Kelley and Firestein’s Textbook of Rheumatology, ed 10. Edited by Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Philadelphia: Elsevier Inc, 2017. pp. 106–125
HA is depolymerized by the action of HA-binding protein involved in HA depolymerization (HYBID) in human skin and synovial fibroblasts independently from hyaluronidases (HYALs) 1 and 2 and CD44.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
, 10- Nagaoka A.
- Yoshida H.
- Nakamura S.
- Morikawa T.
- Kawabata K.
- Kobayashi M.
- Sakai S.
- Takahashi Y.
- Okada Y.
- Inoue S.
Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts.
HYBID was originally reported as a deafness gene (
KIAA1199) of unknown function,
11- Abe S.
- Usami S.
- Nakamura Y.
Mutations in the gene encoding KIAA1199 protein, an inner-ear protein expressed in Deiters' cells and the fibrocytes, as the cause of nonsyndromic hearing loss.
and HYBID is also known as cell migration–inducing protein (CEMIP).
12- Evensen N.A.
- Li Y.
- Kuscu C.
- Liu J.
- Cathcart J.
- Banach A.
- Zhang Q.
- Li E.
- Joshi S.
- Yang J.
- Denoya P.I.
- Pastorekova S.
- Zucker S.
- Shroyer K.R.
- Cao J.
Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP).
HYBID is localized in the clathrin-coated vesicles in skin fibroblasts and contributes to depolymerization of high-molecular-weight HA of approximately 10,000 kDa into intermediate-sized HA fragments of 100 to 10 kDa, which are released to extracellular milieu.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
HYBID is an N-glycosylated protein of 153 kDa composed of one G8, two GG, and four PbH1 domains, lacking substantial homology to HYAL enzymes, HA-binding proteins, HA-link modules, transmembrane domain, and bacterial HYALs. HYBID selectively binds to HA without interaction with chondroitin sulfate A, C, or D; dermatan sulfate; heparin; or heparin sulfate.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
HYBID-mediated degradation of high-molecular-weight HA by synovial fibroblasts may explain the accumulation of lower-molecular-weight HA species in the synovial fluid of patients with joints affected by OA or rheumatoid arthritis.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
However, no or little information is available on HYBID expression or its role in HA degradation in OA cartilage. Transforming growth factor (TGF) β
1 down-regulates
HYBID gene (
CEMIP) expression in skin fibroblasts, but the down-regulation by TGF-β
1 is insufficient in OA and rheumatoid arthritis synovial fibroblasts, suggesting that
HYBID expression is cell-type specific.
10- Nagaoka A.
- Yoshida H.
- Nakamura S.
- Morikawa T.
- Kawabata K.
- Kobayashi M.
- Sakai S.
- Takahashi Y.
- Okada Y.
- Inoue S.
Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts.
Therefore, if
HYBID is expressed in OA chondrocytes, regulation of the gene expression by factors such as cytokines and growth factors remains elusive.
Here, we examined the expression and localization of HYBID in human articular cartilage tissues, and found that HYBID is up-regulated by chondrocytes in HA-depleted areas of the OA cartilage and that immunolocalization of HYBID directly correlates with Mankin score. We also provide evidence that HYBID is implicated in the degradation of high-molecular-weight HA and that among the factors present in OA joints, tumor necrosis factor (TNF)-α up-regulates HYBID expression in OA chondrocytes.
Discussion
In the present study, to the best of our knowledge, we have provided the first evidence that HYBID is overexpressed by chondrocytes in OA articular cartilage. Histologic, histochemical, and immunohistochemical studies demonstrated that chondrocytes located in the HA-proteoglycan–depleted areas of OA cartilage express HYBID protein, and that the degree of HYBID immunostaining–positive chondrocytes directly correlates with cartilage destruction.
Many organs including the brain, skin, lung, testis, and ovary, but not the liver, are known to express the
HYBID gene in humans,
23- Michishita E.
- Garces G.
- Barrett J.C.
- Horikawa I.
Upregulation of the KIAA1199 gene is associated with cellular mortality.
but no information on the expression in articular cartilage was available. In a recent study in HYBID-knockout and wild-type mice, an expression pattern of mouse HYBID similar to that in humans was confirmed, and it was demonstrated that hypertrophic chondrocytes express HYBID during development in wild-type mice, resulting in shorter long bones in the knockout mice.
24- Shimoda M.
- Yoshida H.
- Mizuno S.
- Hirozane T.
- Horiuchi K.
- Yoshino Y.
- Hara H.
- Kanai Y.
- Inoue S.
- Ishijima M.
- Okada Y.
Hyaluronan-binding protein involved in hyaluronan depolymerization controls endochondral ossification through hyaluronan metabolism.
The phenotype was characterized by suppression of the endochondral ossification, which was caused by the inhibition of vascular endothelial growth factor–mediated angiogenesis and osteoclast recruitment by accumulated high-molecular-weight HA in the hypertrophic chondrocyte zone.
24- Shimoda M.
- Yoshida H.
- Mizuno S.
- Hirozane T.
- Horiuchi K.
- Yoshino Y.
- Hara H.
- Kanai Y.
- Inoue S.
- Ishijima M.
- Okada Y.
Hyaluronan-binding protein involved in hyaluronan depolymerization controls endochondral ossification through hyaluronan metabolism.
Chondrocytes in OA articular cartilage are reported to share the characteristics of hypertrophic chondrocytes by expressing hypertrophic chondrocyte markers such as vascular endothelial growth factor and type X collagen.
25- van der Kraan P.M.
- van den Berg W.B.
Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration?.
Accelerated turnover of extracellular matrix components, including proteoglycans and HA, is commonly observed both in the hypertrophic chondrocyte zone of the developing growth plate
26- Mwale F.
- Billinghurst C.
- Wu W.
- Alini M.
- Webber C.
- Reiner A.
- Ionescu M.
- Poole J.
- Poole A.R.
Selective assembly and remodelling of collagens II and IX associated with expression of the chondrocyte hypertrophic phenotype.
, 27- Pratta M.A.
- Yao W.
- Decicco C.
- Tortorella M.D.
- Liu R.Q.
- Copeland R.A.
- Magolda R.
- Newton R.C.
- Trzaskos J.M.
- Arner E.C.
Aggrecan protects cartilage collagen from proteolytic cleavage.
and in OA articular cartilage.
1Aggrecanases and cartilage matrix degradation.
, 2Okada Y: Proteinases and matrix degradation. Kelley and Firestein’s Textbook of Rheumatology, ed 10. Edited by Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Philadelphia: Elsevier Inc, 2017. pp. 106–125
Therefore, the finding of HYBID expression by OA chondrocytes located in the HA-deleted area suggests the possible involvement of HYBID in HA degradation in OA cartilage.
Two HYALs (1 and 2) and HA receptor CD44 were originally thought to be crucial to HA degradation through the following steps: high-molecular-weight HA is captured by CD44 on cell surfaces, concentrated in the caveolin-rich lipid rafts, and cleaved by HYAL2 into intermediate-size fragments, which are then transported to lysosomes and finally digested into oligosaccharides by lysosomal enzyme HYAL1.
28- Dicker K.T.
- Gurski L.A.
- Pradhan-Bhatt S.
- Witt R.L.
- Farach-Carson M.C.
- Jia X.
Hyaluronan: a simple polysaccharide with diverse biological functions.
, 29- Hascall V.C.
- Wang A.
- Tammi M.
- Oikari S.
- Tammi R.
- Passi A.
- Vigetti D.
- Hanson R.W.
- Hart G.W.
The dynamic metabolism of hyaluronan regulates the cytosolic concentration of UDP-GlcNAc.
However, since this model was proposed based on the data of the experiments using a breast carcinoma cell line
30- Bourguignon L.Y.
- Singleton P.A.
- Diedrich F.
- Stern R.
- Gilad E.
CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion.
and cells stably transfected with these genes,
31CD44-dependent intracellular and extracellular catabolism of hyaluronic acid by hyaluronidase-1 and -2.
and because neither HYAL1 nor HYAL2 is expressed in the brain that contains a large amount of HA,
32- Csoka A.B.
- Scherer S.W.
- Stern R.
Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31.
, 33- Triggs-Raine B.
- Salo T.J.
- Zhang H.
- Wicklow B.A.
- Natowicz M.R.
Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX.
the HYAL2/CD44 and HYAL1 system was known to have limitations for the explanation of the rapid catabolism of HA
in vivo.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
Thus, pathways different from this system were expected to be involved in HA degradation within tissues such as the brain. New HA-degrading pathways were explored and it was verified that HYBID plays a central role in HA degradation independently from HYAL1 and HYAL2/CD44 axis in skin and synovial fibroblasts.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
In the present study,
HYAL1,
HYAL2, and
CD44 were also up-regulated in OA cartilage tissue, and knockdown of
HYAL2 partially decreased HA-degrading activity in OA chondrocytes, suggesting a potential role of HYAL2 in HA degradation. However, since knockdown of
HYAL1 or
CD44 resulted in negligible suppression of HA-degrading activity, it seems unlikely that the HYAL2/CD44 and HYAL1 system is a central pathway for HA degradation in OA chondrocytes. On the other hand, OA chondrocytes showed almost complete disappearance of the activity by knockdown of the HYBID expression, co-localization of HYBID with the clathrin heavy chain, and rapid vesicle endocytosis of high-molecular-weight HA. Thus, our data strongly suggest that HYBID is involved in the HA degradation by OA chondrocytes, as we have demonstrated in skin and synovial fibroblasts.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
Up-regulation of HYBID in OA cartilage suggests the possibility that the expression by chondrocytes is regulated by factors such as proinflammatory cytokines and growth factors, which are commonly produced in OA joint tissues. Therefore, the effects of eight factors (TNF-α, TGF-β
1, IL-1α, histamine, insulin-like growth factor 1, vascular endothelial growth factor, basic fibroblast growth factor, and prostaglandin E
2) on HYBID gene expression were studied, and it was found that the expression is promoted only by TNF-α treatment. HYBID was originally identified in human skin fibroblasts as a molecule that is strikingly up-regulated and down-regulated by histamine and TGF-β
1, respectively.
9- Yoshida H.
- Nagaoka A.
- Kusaka-Kikushima A.
- Tobiishi M.
- Kawabata K.
- Sayo T.
- Sakai S.
- Sugiyama Y.
- Enomoto H.
- Okada Y.
- Inoue S.
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
HYBID expression in human skin fibroblasts is down-regulated most efficiently by TGF-β
1 and to some extent by basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor BB.
10- Nagaoka A.
- Yoshida H.
- Nakamura S.
- Morikawa T.
- Kawabata K.
- Kobayashi M.
- Sakai S.
- Takahashi Y.
- Okada Y.
- Inoue S.
Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts.
However, the down-regulation by TGF-β
1 is negligible in arthritic synovial fibroblasts.
10- Nagaoka A.
- Yoshida H.
- Nakamura S.
- Morikawa T.
- Kawabata K.
- Kobayashi M.
- Sakai S.
- Takahashi Y.
- Okada Y.
- Inoue S.
Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts.
According to the different responses to growth factors, regulation of
HYBID gene expression was suggested to be cell-type specific.
10- Nagaoka A.
- Yoshida H.
- Nakamura S.
- Morikawa T.
- Kawabata K.
- Kobayashi M.
- Sakai S.
- Takahashi Y.
- Okada Y.
- Inoue S.
Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts.
In the present study, no definite changes in
HYBID expression were obtained in OA chondrocytes treated with TGF-β
1, basic fibroblast growth factor, or histamine. In human cancer cell lines such as breast carcinoma cells, hypomethylation of the
HYBID (
KIAA1199) promoter region is reported to link to
HYBID overexpression.
34- Kuscu C.
- Evensen N.
- Kim D.
- Hu Y.J.
- Zucker S.
- Cao J.
Transcriptional and epigenetic regulation of KIAA1199 gene expression in human breast cancer.
In colon carcinoma cells, hypoxia is known to promote
HYBID (
CEMIP) expression by binding of hypoxia-inducible factor 2α to the hypoxia response element within the promoter region through increased presence of H3K4me3 in the promoter.
12- Evensen N.A.
- Li Y.
- Kuscu C.
- Liu J.
- Cathcart J.
- Banach A.
- Zhang Q.
- Li E.
- Joshi S.
- Yang J.
- Denoya P.I.
- Pastorekova S.
- Zucker S.
- Shroyer K.R.
- Cao J.
Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP).
Therefore,
HYBID expression in OA chondrocytes may also be regulated by the epigenetic mechanism. On the other hand, the promoter region of the
HYBID gene contains activator protein 1 and NF-κB binding sites, and these elements are known to be essential to
HYBID gene expression in breast carcinoma cells.
34- Kuscu C.
- Evensen N.
- Kim D.
- Hu Y.J.
- Zucker S.
- Cao J.
Transcriptional and epigenetic regulation of KIAA1199 gene expression in human breast cancer.
Since activator protein 1 and NF-κB are the major transcription factors of soluble TNF-α–TNF receptor 1-complex I signaling,
35- Kalliolias G.D.
- Ivashkiv L.B.
TNF biology, pathogenic mechanisms and emerging therapeutic strategies.
HYBID expression after stimulation with TNF-α in OA chondrocytes may be caused through this pathway, although detailed further studies are needed to clarify the intracellular signaling pathways for the regulation of
HYBID gene expression.
The present study had potential limitations. HA in articular cartilage is present as the HA-aggrecan network structure, which is formed by the association of aggrecan molecules with HA chain.
2Okada Y: Proteinases and matrix degradation. Kelley and Firestein’s Textbook of Rheumatology, ed 10. Edited by Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Philadelphia: Elsevier Inc, 2017. pp. 106–125
, 3Drug insight: aggrecanases as therapeutic targets for osteoarthritis.
In the present study, high-molecular-weight HA was used for HA digestion by OA chondrocytes. If aggrecan of the HA-aggrecan network in OA cartilage is digested by metalloproteinases such as a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 before HA degradation by HYBID, the data may fulfill the requirements for HA digestion by HYBID in the cartilage. However, since no information is available on sequential digestion of aggrecan and HA in OA cartilage, how HA in the HA-aggrecan network structure is degraded by HYBID in cartilage tissue deserves to be further investigated. Nonetheless, HA degradation in the hypertrophic chondrocyte zone is mediated by HYBID expression,
24- Shimoda M.
- Yoshida H.
- Mizuno S.
- Hirozane T.
- Horiuchi K.
- Yoshino Y.
- Hara H.
- Kanai Y.
- Inoue S.
- Ishijima M.
- Okada Y.
Hyaluronan-binding protein involved in hyaluronan depolymerization controls endochondral ossification through hyaluronan metabolism.
and thus it is plausible that HA in the HA-aggrecan network may be degraded by the action of HYBID in the OA cartilage tissue. Another question is how the HA-aggrecan network structure remote from chondrocytes is degraded. The recent study showing that HYAL2 is secreted and has weak HA-degrading activity at neutral pH
36- Hida D.
- Danielson B.T.
- Knudson C.B.
- Knudson W.
CD44 knock-down in bovine and human chondrocytes results in release of bound HYAL2.
suggests the possibility that HYAL2 may be involved in HA degradation in the interterritorial zone. However, further studies are definitely necessary to fully elucidate the catabolic mechanisms of HA in the HA-aggrecan network at the molecular and cellular levels within articular cartilage.
In summary, we have demonstrated that HYBID is overexpressed by chondrocytes in the HA-depleted areas of OA cartilage with a direct correlation with Mankin score, and that HYBID expression is up-regulated by TNF-α in OA chondrocytes. Accumulated lines of evidence have indicated that extracellular matrix–degrading metalloproteinases, including collagenolytic matrix metalloproteinases and aggrecanolytic a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5, play central roles in the degradation of collagens and aggrecan in OA cartilage.
2Okada Y: Proteinases and matrix degradation. Kelley and Firestein’s Textbook of Rheumatology, ed 10. Edited by Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Philadelphia: Elsevier Inc, 2017. pp. 106–125
, 3Drug insight: aggrecanases as therapeutic targets for osteoarthritis.
, 27- Pratta M.A.
- Yao W.
- Decicco C.
- Tortorella M.D.
- Liu R.Q.
- Copeland R.A.
- Magolda R.
- Newton R.C.
- Trzaskos J.M.
- Arner E.C.
Aggrecan protects cartilage collagen from proteolytic cleavage.
On the other hand, the present study has provided, to the best of our knowledge, the first data that HYBID is involved in HA degradation in OA cartilage and may be a molecular target in OA patients. Since HYBID expression and activity are up-regulated by TNF-α, one possible therapeutic strategy may be the application of TNF-α blockade, which has been reported to be effective both for the prevention of TNF-α–induced cartilage damage in a preclinical study
37- Urech D.M.
- Feige U.
- Ewert S.
- Schlosser V.
- Ottiger M.
- Polzer K.
- Schett G.
- Lichtlen P.
Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNF{alpha} single-chain Fv antibody (ESBA105) designed for local therapeutic use.
and for the treatment of a patient with inflammatory knee OA.
38- Grunke M.
- Schulze-Koops H.
Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade.
In addition, the development of inhibitors selective to HYBID or molecules to down-regulate expression might be another option, although deliberate and detailed analyses of the function of HYBID in pathophysiologic conditions are still needed for clarification.
Article Info
Publication History
Published online: June 20, 2018
Accepted:
May 22,
2018
Footnotes
Supported by the Japan Society for the Promotion of Science Grants-in-aid for Scientific Research 16H05454 (Y.O.) and 16K08719 (M.S.).
H.S. and M.S. contributed equally to this work.
Disclosures: H.Y. is an employee of Kao Corporation and a holder of the HYBID patent.
Copyright
© 2018 American Society for Investigative Pathology. Published by Elsevier Inc.