KR20230088665A - Pharmaceutical composition for treating temporomandibular joint osteoarthritis comprising Vitamin D - Google Patents
Pharmaceutical composition for treating temporomandibular joint osteoarthritis comprising Vitamin D Download PDFInfo
- Publication number
- KR20230088665A KR20230088665A KR1020230075417A KR20230075417A KR20230088665A KR 20230088665 A KR20230088665 A KR 20230088665A KR 1020230075417 A KR1020230075417 A KR 1020230075417A KR 20230075417 A KR20230075417 A KR 20230075417A KR 20230088665 A KR20230088665 A KR 20230088665A
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- KR
- South Korea
- Prior art keywords
- osteoarthritis
- temporomandibular joint
- vitamin
- joint osteoarthritis
- present
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- 210000001738 temporomandibular joint Anatomy 0.000 title claims abstract description 56
- 229930003316 Vitamin D Natural products 0.000 title claims abstract description 41
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- 235000019166 vitamin D Nutrition 0.000 title claims abstract description 41
- 239000011710 vitamin D Substances 0.000 title claims abstract description 41
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/82—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving vitamins or their receptors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/10—Musculoskeletal or connective tissue disorders
- G01N2800/105—Osteoarthritis, e.g. cartilage alteration, hypertrophy of bone
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Abstract
본 발명은 비타민 D를 유효성분으로 함유하는 조성물을 턱관절 골관절염 치료용 약학조성물 및 건강식품으로 제공할 수 있으며, 턱관절 골관절염 진단 또는 예후 예측용 바이오마커 조성물에 관한 것으로, 보다 상세하게는 초기 턱관절 골관절염이 발병된 환자군에서 비타민 D의 결핍이 확인되었으며, 1년 후 추적검사에서 비타민 D 함량 증가에 따라, 턱관절 골관절염 진행이 개선된 것이 확인됨에 따라, 비타민 D를 유효성분으로 함유하는 조성물을 턱관절 골관절염 치료제로 제공될 수 있으며, 혈액 내 비타민 D의 함량 변화는 턱관절 골관절염의 진단 또는 예후 예측용 바이오마커 조성물로 제공될 수 있다.The present invention can provide a composition containing vitamin D as an active ingredient as a pharmaceutical composition and health food for treating osteoarthritis of the temporomandibular joint, and relates to a biomarker composition for diagnosing or predicting the prognosis of osteoarthritis of the temporomandibular joint, and more particularly, in the early jaw joint Deficiency of vitamin D was confirmed in the patient group with joint osteoarthritis, and as it was confirmed that the progress of temporomandibular joint osteoarthritis was improved according to the increase in vitamin D content in the follow-up test after 1 year, a composition containing vitamin D as an active ingredient was prepared. It can be provided as a therapeutic agent for temporomandibular joint osteoarthritis, and changes in the content of vitamin D in blood can be provided as a biomarker composition for diagnosis or prognosis of temporomandibular joint osteoarthritis.
Description
본 발명은 비타민 D를 유효성분으로 함유하는 조성물을 턱관절 골관절염 치료용 약학조성물 및 건강식품으로 제공할 수 있으며, 턱관절 골관절염 진단 또는 예후예측용 바이오마커 조성물로 제공하는 기술이다.The present invention provides a composition containing vitamin D as an active ingredient as a pharmaceutical composition and health food for treating osteoarthritis of the temporomandibular joint, and as a biomarker composition for diagnosing or predicting the prognosis of osteoarthritis of the temporomandibular joint.
골관절염 (osteoarthritis)이란 관절면의 연골 (articular cartilage)의 점진적 손상 및 하방의 연골하골 (subchondral bone)의 퇴행성 변화를 지칭한다. 턱관절의 골관절염은 여성에게서 호발하며 무릎이나 손가락, 고관절 등에 나타나는 골관절염과는 유병율에 있어서 독특한 차이가 있는데, 성장이 완료되지 않은 어린 나이에도 나타날 수 있으며 20대 여성에게서 다른 연령대와 비교하여 비교적 높은 유병율을 보인다는 점이다. Osteoarthritis refers to progressive damage of articular cartilage and degenerative changes of subchondral bone below. Osteoarthritis of the temporomandibular joint occurs predominantly in women and has a unique difference in prevalence from osteoarthritis that occurs in the knee, finger, and hip joints. is that it shows
턱관절 퇴행성 골관절염은 진행할 경우 과두 흡수 (resorption) 및 피질골 박리 (erosion)로 인하여 교합 변화 및 안모의 변화를 동반할 수 있다. 이렇게 발생한 교합 변화 및 안모 변화는 노년층뿐 만 아니라 10대 및 20대 환자들에게서도 심미적 문제와 저작 기능 감소로 이어질 수 있으며, 이는 삶의 질 (quality of life)에 지대한 영향을 미칠 수 있다는 점에서 턱관절 골관절염의 조기 진단 및 치료는 매우 중요하다.Degenerative osteoarthritis of the temporomandibular joint may be accompanied by changes in occlusion and facial features due to condyle resorption and cortical bone erosion. Occlusal changes and facial changes that occur in this way can lead to aesthetic problems and reduced masticatory function not only in the elderly but also in patients in their teens and 20s, which can have a great impact on the quality of life. Early diagnosis and treatment of joint osteoarthritis is very important.
현재까지의 턱관절 골관절염의 치료 방법은 저작 부하를 줄이는 방법 (교합안정장치, 물리치료, 습관조절 등)을 통해 턱관절 과두 재형성 (remodeling)을 유도하는 방향이 가장 일반적이며 비스테로이드성 항염증제 (Non-steroidal anti-inflammatory drugs, NSAID)나 근이완제를 포함하는 약물치료는 통증을 경감시키기 위해 사용할 수는 있으나 과두 재형성을 위해 적용되지는 않으며, 아직까지 턱관절 골관절염 치료에 적용시킬 수 있는 치료 물질에 대한 연구 및 개발은 미비한 실정이다.Until now, treatment methods for temporomandibular joint osteoarthritis are most common in the direction of inducing remodeling of the temporomandibular joint through methods of reducing the masticatory load (occlusion stabilizers, physical therapy, habit control, etc.), and nonsteroidal anti-inflammatory drugs ( Non-steroidal anti-inflammatory drugs (NSAIDs) or drug therapy including muscle relaxants can be used to relieve pain, but are not applied for condylar remodeling, and are still applicable to the treatment of temporomandibular joint osteoarthritis. Research and development on it is incomplete.
본 발명은 효과적인 턱관절 골관절염 치료를 위해, 비타민 D를 유효성분으로 함유하는 조성물을 턱관절 골관절염 치료제로 제공하며, 턱관절 골관절염 개선용 건강식품으로 제공하고자 한다.The present invention is intended to provide a composition containing vitamin D as an active ingredient for effective treatment of temporomandibular joint osteoarthritis as a treatment for temporomandibular joint osteoarthritis and as a health food for improving temporomandibular osteoarthritis.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 치료용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for the treatment of temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 개선용 건강식품을 제공한다.The present invention provides a health food for improving temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 진단용 바이오마커 조성물을 제공한다.The present invention provides a biomarker composition for diagnosing temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 예후 예측용 바이오마커 조성물을 제공한다.The present invention provides a biomarker composition for predicting the prognosis of temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
본 발명은 비타민 D의 수준을 검출하는 제제를 유효성분으로 함유하는 턱관절 골관절염 진단 또는 예후 예측용 키트를 제공한다.The present invention provides a kit for diagnosing or predicting the prognosis of temporomandibular joint osteoarthritis, containing an agent for detecting the level of vitamin D as an active ingredient.
또한, 본 발명은 검체로부터 분리된 시료로부터 비타민 D 수준을 확인하는 단계; 및 상기 발현 수준을 대조군과 비교하는 단계를 포함하는 턱관절 골관절염 진단 또는 예후 예측에 정보를 제공하는 방법을 제공한다.In addition, the present invention comprises the steps of confirming the level of vitamin D from the sample separated from the specimen; And it provides a method for providing information for diagnosing or predicting prognosis of temporomandibular joint osteoarthritis, comprising comparing the expression level with a control group.
본 발명에 따르면, 초기 턱관절 골관절염이 발병된 환자군에서 비타민 D의 혈중 농도가 상대적으로 감소된 것이 확인되었으며, 1년 후 추적검사에서 비타민 D 함량 증가에 따라, 턱관절 골관절염 진행이 개선된 것이 확인됨에 따라, 비타민 D를 유효성분으로 함유하는 조성물을 턱관절 골관절염 치료제로 제공될 수 있으며, 혈액 내 비타민 D의 함량 변화는 턱관절 골관절염의 진단 또는 예후 예측용 바이오마커 조성물로 제공될 수 있다.According to the present invention, it was confirmed that the blood concentration of vitamin D was relatively reduced in the patient group with early temporomandibular joint osteoarthritis, and the progress of temporomandibular joint osteoarthritis was improved according to the increase in vitamin D content in the follow-up test after 1 year. Accordingly, a composition containing vitamin D as an active ingredient may be provided as a therapeutic agent for temporomandibular joint osteoarthritis, and changes in the content of vitamin D in blood may be provided as a biomarker composition for diagnosis or prognosis of temporomandibular joint osteoarthritis.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
종래 동물 실험을 통한 연구결과에서 비타민 D의 활성체가 염증성 사이토카인 (cytokine)의 분비를 조절하여 턱관절 골관절염의 발병에 영향을 미칠 수 있다는 사실은 밝혀진 바 있으나, 골관절염의 진행에 따라 비타민 D가 어떠한 영향을 미치는가에 대해서는 확인된 바가 없다.Previous research results through animal experiments have shown that the activator of vitamin D can affect the development of temporomandibular joint osteoarthritis by regulating the secretion of inflammatory cytokines. It has not been confirmed whether it has any effect.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 치료용 약학조성물을 제공할 수 있다.The present invention can provide a pharmaceutical composition for treating temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
상기 턱관절 골관절염은 병의 초기 단계일 수 있으나, 이에 제한되는 것은 아니다.The temporomandibular joint osteoarthritis may be an early stage of the disease, but is not limited thereto.
상기 비타민 D는 25-디하이드록시비타민 D (25-dihydroxyvitamine D)일 수 있으나, 이에 제한되는 것은 아니다.The vitamin D may be 25-dihydroxyvitamine D, but is not limited thereto.
본 발명의 한 구체예에서, 상기 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 치료용 약학조성물은 통상적인 방법에 따라 주사제, 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다.In one embodiment of the present invention, the pharmaceutical composition for the treatment of temporomandibular joint osteoarthritis containing vitamin D as an active ingredient is an injection, granule, powder, tablet, pill, capsule, suppository, gel, suspension, Any one formulation selected from the group consisting of emulsions, drops, and liquids may be used.
본 발명의 다른 구체예에서, 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 치료용 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention, the pharmaceutical composition for the treatment of temporomandibular joint osteoarthritis containing vitamin D as an active ingredient is suitable carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents and lubricants commonly used in the manufacture of pharmaceutical compositions. , Flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, may further include one or more additives selected from the group consisting of binders and lubricants.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil may be used, and solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. These solid preparations may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base material of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
본 발명의 일실시예에 따르면 상기 약학 조성물은 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition is administered in a conventional manner through intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes. can be administered to the subject as
상기 비타민 D의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferred dose of vitamin D may vary depending on the condition and weight of the subject, the type and severity of the disease, the type of drug, the route and duration of administration, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, but not limited thereto, the daily dosage may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or divided into several administrations, and the scope of the present invention is not limited thereby.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited to these examples.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 개선용 건강식품을 제공할 수 있다.The present invention can provide a health food for improving temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
상기 건강식품은 상기 비타민 D 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.The health food is used together with other foods or food additives in addition to the vitamin D, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use thereof, for example, prevention, health or therapeutic treatment.
상기 건강식품에 함유된 화합물의 유효용량은 상기 치료제의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the health food may be used according to the effective dose of the therapeutic agent, but may be less than the above range in the case of long-term intake for the purpose of health and hygiene or health control. Since there is no problem in terms of safety, it is certain that the components can be used in an amount greater than the above range.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제등을 들 수 있다.There is no particular limitation on the type of health food, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes; and the like.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 진단용 바이오마커 조성물을 제공할 수 있다.The present invention can provide a biomarker composition for diagnosing temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
상기 턱관절 골관절염은 초기 턱관절 골관절염 단계를 진단하는 것일 수 있다.The temporomandibular joint osteoarthritis may be diagnosed in an early stage of temporomandibular joint osteoarthritis.
본 발명은 비타민 D를 유효성분으로 함유하는 턱관절 골관절염 예후 예측용 바이오마커 조성물을 제공할 수 있다.The present invention can provide a biomarker composition for predicting the prognosis of temporomandibular joint osteoarthritis containing vitamin D as an active ingredient.
상기 바이오마커 조성물은 턱관절 골관절염의 초기 단계에서 중증도 단계로의 진행을 예측하는 것일 수 있다.The biomarker composition may predict progression of temporomandibular joint osteoarthritis from an early stage to a severe stage.
본 발명은 비타민 D의 수준을 검출하는 제제를 유효성분으로 함유하는 턱관절 골관절염 진단 또는 예후 예측용 키트를 제공할 수 있다.The present invention can provide a kit for diagnosing or predicting the prognosis of temporomandibular joint osteoarthritis, containing an agent for detecting the level of vitamin D as an active ingredient.
또한, 본 발명은 검체로부터 분리된 시료로부터 비타민 D 수준을 확인하는 단계; 및 상기 발현 수준을 대조군과 비교하는 단계를 포함하는 턱관절 골관절염 진단 또는 예후 예측에 정보를 제공하는 방법을 제공할 수 있다.In addition, the present invention comprises the steps of confirming the level of vitamin D from the sample separated from the specimen; And it can provide a method for providing information for diagnosing or predicting prognosis of temporomandibular joint osteoarthritis, comprising comparing the expression level with a control group.
상기 검체로부터 분리된 시료는 혈액, 혈청 및 혈장으로 이루어진 군에서 선택되는 것일 수 있으나, 이에 제한되는 것은 아니다.A sample separated from the specimen may be selected from the group consisting of blood, serum and plasma, but is not limited thereto.
상기 발현 수준은 웨스턴 블랏팅(western blotting), ELISA(enzyme linked immunosorbent assay), 방사선면역분석법(Radioimmunoassay), 방사면역 확산법(Radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역 확산법, 로케트(Rocket) 면역전기영동, 조직면역 염색, 면역침전분석법(immunoprecipitation assay), 보체 고정 분석법(complete fixation assay), 유세포분석법(Fluorescence Activated Cell Sorter, FACS) 및 단백질 칩(protein chip) 분석법으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 측정되는 것일 수 있으나, 이에 제한되는 것은 아니다.The expression level was determined by western blotting, enzyme linked immunosorbent assay (ELISA), radioimmunoassay, radioimmunodiffusion, Ouchterlony immunodiffusion method, Rocket immunoelectrolysis. By one or more methods selected from the group consisting of electrophoresis, tissue immunostaining, immunoprecipitation assay, complete fixation assay, flow cytometry (Fluorescence Activated Cell Sorter, FACS) and protein chip assay It may be measured, but is not limited thereto.
본 발명의 "바이오마커"는 턱관절 골관절염이 발생한 대상체의 시료를 정상 대조군의 시료와 구분하여 진단할 수 있는 물질로, 정상 대조군에 비하여 질환이 발생한 대상체의 조직, 세포 또는 혈액에서 증가 또는 감소 양상을 보이는 단백질 또는 핵산, 지질, 당지질, 당단백질 등과 같은 유기 생체 분자 등을 포함한다.The "biomarker" of the present invention is a substance that can be diagnosed by distinguishing a sample of a subject with temporomandibular joint osteoarthritis from a sample of a normal control group, and increases or decreases in the tissue, cell or blood of a subject with the disease compared to a normal control group. It includes organic biomolecules such as proteins or nucleic acids, lipids, glycolipids, glycoproteins, etc.
본 발명의 "예후"는 병세의 진행, 회복에 관한 예측을 의미하는 것으로, 전망 내지는 예비적 평가를 말한다. 본 발명의 목적상, 예후란 턱관절 골관절염의 치료 후 해당 개체에서 골관절염 진행 여부 등을 판단하는 것을 의미한다.The "prognosis" of the present invention refers to prediction of disease progression and recovery, and refers to prospective or preliminary evaluation. For the purpose of the present invention, prognosis means determining whether or not osteoarthritis progresses in a subject after treatment for temporomandibular joint osteoarthritis.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
하기의 실험예들은 본 발명에 따른 각각의 실시예에 공통적으로 적용되는 실험예를 제공하기 위한 것이다.The following experimental examples are intended to provide experimental examples commonly applied to each embodiment according to the present invention.
<실험예 1> 연구참여자<Experimental Example 1> Research participant
총 59명의 20대 여성 (mean age, 23.4 ± 3.4 years; age range, 20 - 29 years)이 참여하였으며 이 중 43명은 전산화 단층촬영 (CT)을 통해 턱관절 퇴행성 골관절염으로 진단된 여성 환자이며 16명은 턱관절 장애 및 턱관절 골관절염 증상이 없는 자발적 참여자로 구성되었다. 턱관절 골관절염의 진단은 Diagnostic Criteria for Temporomandibular Disorder (DC/TMD) Axis I에 기반하여 구강내과 전문의에 의해 이루어졌다. 초진 시 모든 연구참여자들에게서 CT 촬영 및 혈액 및 요 검체의 채취를 시행하였고 1년 뒤 추적 관찰 시 턱관절 골관절염 환자 43명 중 5명, 건강인 중 4명이 참여 의사를 철회하여 총 50 명의 연구참여자에게 동일한 과정이 시행되었다. A total of 59 women in their 20s (mean age, 23.4 ± 3.4 years; age range, 20 - 29 years) participated, 43 of whom were diagnosed with temporomandibular joint degenerative osteoarthritis through computed tomography (CT), and 16 were female patients. Voluntary participants without symptoms of temporomandibular joint disorder or temporomandibular osteoarthritis were included. The diagnosis of temporomandibular osteoarthritis was made by an oral surgeon based on the Diagnostic Criteria for Temporomandibular Disorder (DC/TMD) Axis I. At the time of the initial diagnosis, CT scan and blood and urine specimen collection were performed on all study participants, and at follow-up one year later, 5 out of 43 patients with temporomandibular joint osteoarthritis and 4 out of 4 healthy people withdrew their intention to participate, resulting in a total of 50 research participants. The same process was carried out for
<실험예 2> 턱관절 골관절염 진행 평가<Experimental Example 2> Evaluation of progression of temporomandibular joint osteoarthritis
턱관절 골관절염의 진단은 CT를 통해 이루어졌으며 진행 정도에 따라 초진 시 골관절염이 관찰되지 않는 과두(Condyle)는 대조군(Control), 초기 퇴행성 골변화를 보이는 과두는 iniTMJOA군, 중등도 이상의 골변화를 보이는 경우는 sevTMJOA군으로 분류하였다. The diagnosis of temporomandibular joint osteoarthritis was made through CT, and according to the degree of progression, condyles with no osteoarthritis at the first examination were classified as a control group, condyles with early degenerative bone changes in the iniTMJOA group, and those with moderate or more severe bone changes with sevTMJOA. classified into groups.
골관절염 진행의 평가는 정성적 및 정량적 방법을 모두 사용하였다. 정성적 평가는 CT 판독자의 주관에 의존하여 1년 뒤 턱관절 골관절염이 진행 되었는지, 그렇지 않은지를 기준으로 평가하였고 정량적 평가는 CT 결과를 3차원 재건하여 초진 시의 CT와 1년 뒤 추적 관찰 시의 CT를 중첩하는 형태로 부피 변화를 측정하는 방식으로 이루어졌다. Assessment of osteoarthritis progression was performed using both qualitative and quantitative methods. The qualitative evaluation depended on the subjectivity of the CT reader and evaluated whether or not the temporomandibular joint osteoarthritis had progressed after 1 year or not. The quantitative evaluation was performed by 3-dimensional reconstruction of the CT results, and the CT at the initial diagnosis and the follow-up after 1 year were evaluated. It was done by measuring the volume change in the form of overlapping CT.
정성적 평가를 위해 연구참여자의 각 과두를 3 그룹으로 나누었다. 초진 시 골관절염이 관찰되지 않았고 1년 뒤 추적 관찰 시에도 관찰되지 않았던 과두는 Normal, 초진 시 골관절염이 관찰되었으나 진행하지 않은 과두는 noproTMJOA, 초진 시 골관절염이 관찰되었고 1년 뒤 추적 관찰에서 진행이 관찰된 과두는 proTMJOA로 분류하였다. For qualitative evaluation, each condyle of the research participants was divided into 3 groups. Osteoarthritis was not observed at the initial diagnosis and was not observed at follow-up 1 year later: normal; osteoarthritis was observed at the first visit but did not progress; The condyles were classified as proTMJOA.
정량적 평가를 위하여 초진 시 및 1년 뒤 추적 관찰 시 촬영한 CT 영상을 3차원 재건하여 중첩하여 부피 변화량을 측정하였다. For quantitative evaluation, the amount of volume change was measured by overlaying 3-dimensional reconstruction of CT images taken at the first visit and at the follow-up after 1 year.
<실험예 3> 비타민 D (25-dihydroxyvitamin D) 농도 측정<Experimental Example 3> Vitamin D (25-dihydroxyvitamin D) concentration measurement
정맥혈의 채취는 오전 8시에서 11시 사이에 이루어졌으며 공복 상태로 시행되었다. 혈중 25-dihydroxyvitamine D의 농도는 화학발광 미세입자 면역분석법 (chemiluminescent microparticle immunoassay; Abbot, Singapore)을 통해 측정하였다. Venous blood collection was performed between 8:00 and 11:00 am and was performed in an empty stomach. The concentration of 25-dihydroxyvitamine D in blood was measured by chemiluminescent microparticle immunoassay (Abbot, Singapore).
<실험예 4> 통계학적 분석<Experimental Example 4> Statistical analysis
비타민 D의 치료제로서의 가치를 평가하기 위하여 초진 시 골관절염의 유무 및 정도의 차이에 기반하여 나눈 세 군 (Control, iniTMJOA, sevTMJOA) 간 혈중 농도의 차이를 one-way ANOVA를 통하여 분석하였다. To evaluate the value of vitamin D as a therapeutic agent, the difference in blood concentration between the three groups (Control, iniTMJOA, and sevTMJOA) divided based on the difference in the presence and severity of osteoarthritis at the time of initial diagnosis was analyzed through one-way ANOVA.
비타민 D와 턱관절 골관절염의 정성적 진행 정도와의 관계 평가를 위해서는 골관절염 진행 정도에 따라 분류한 3군 (Normal, noproTMJOA, proTMJOA) 간의 차이를 비교하기 위해 repeated measure ANOVA가 사용되었고 정량적 진행 정도와의 관계 평가를 위해서는 multivariate linear effect model이 사용되었다.To evaluate the relationship between vitamin D and the qualitative progression of temporomandibular joint osteoarthritis, repeated measures ANOVA was used to compare the differences between the three groups (Normal, noproTMJOA, proTMJOA) classified according to the degree of osteoarthritis progression, and quantitative progression A multivariate linear effect model was used to evaluate the relationship.
<실시예 1> 턱관절 골관절염과 비타민 D의 관련성 확인<Example 1> Confirmation of relationship between temporomandibular joint osteoarthritis and vitamin D
턱관절 골관절염 환자와 정상인의 혈중 비타민 D 농도 차이를 확인하기 위해, 턱관절 골관절염 여부 및 진행 정도에 따라 분류한 3군 간 혈중 25-dihydroxyvitamin D의 농도를 비교하였다. To examine the difference in serum vitamin D concentrations between patients with temporomandibular joint osteoarthritis and normal subjects, serum concentrations of 25-dihydroxyvitamin D were compared between three groups classified according to the prevalence and progression of temporomandibular joint osteoarthritis.
그 결과, 표 1과 같이 3군 간 유의미한 차이를 나타내었으며 특히, 초기 턱관절 골관절염에 의한 골변화를 나타내는 iniTMJOA군은 정상 대조군과 비교하여 비타민 D 농도가 감소된 것을 확인할 수 있었다.As a result, as shown in Table 1, there was a significant difference between the 3 groups, and in particular, the iniTMJOA group showing bone changes due to early temporomandibular joint osteoarthritis showed a decrease in vitamin D concentration compared to the normal control group.
상기 결과로부터 비타민 D 농도 감소 수준 확인을 통하여 초기 턱관절 골관절염을 진단할 수 있으며, 초기 턱관절 골관절염 치료를 위해 비타민 D 투여가 제안될 수 있다.From the above results, it is possible to diagnose the initial temporomandibular joint osteoarthritis by confirming the reduced level of the vitamin D concentration, and vitamin D administration can be suggested for the treatment of the initial temporomandibular joint osteoarthritis.
Descriptive values are shown as mean ± SD.Descriptive values are shown as mean ± SD.
Data obtained from one-way ANOVA with Bonferonni’s post-hoc analysis.Data obtained from one-way ANOVA with Bonferonni’s post-hoc analysis.
* P < 0.05, ** P < 0.001 by one-way ANOVA with Bonferonni’s post-hoc analysis.* P < 0.05, ** P < 0.001 by one-way ANOVA with Bonferonni’s post-hoc analysis.
<실시예 2> 턱과절 골관절염 진행에 따른 비타민 D 농도 변화 확인<Example 2> Confirmation of changes in vitamin D concentration according to the progression of mandibular osteoarthritis
반복측정분산분석 (Repeated measure ANOVA)을 이용한 정성적 분석 결과, 표 2와 같이 정상 (Normal), noproTMJOA 및 proTMJOA 3군 간 유의미한 time * group interaction이 확인됨에 따라, 시간 변화에 따른 그룹간 유의미한 농도의 차이가 확인되었다. 특히, 초기 턱관절 골관절염이 확인되었으나, 1년 후 골관절염이 더 이상 진행되지 않은 noproTMJOA군의 1년 후 추적 검사에서 비타민 D 농도가 다른 군에 비해 유의미하게 증가된 것이 확인되는 바, 상기 결과로부터 비타민 D는 초기 턱관절 골관절염의 치료를 위한 치료제로 사용될 수 있음이 확인되었다.As a result of qualitative analysis using repeated measures ANOVA, as shown in Table 2, a significant time * group interaction was confirmed between the 3 groups of Normal, noproTMJOA and proTMJOA. difference was confirmed. In particular, in a follow-up test after 1 year in the noproTMJOA group, in which osteoarthritis of the temporomandibular joint was confirmed in the early stage, but the osteoarthritis did not progress after 1 year, it was confirmed that the vitamin D concentration was significantly increased compared to the other groups. It was confirmed that D can be used as a therapeutic agent for the treatment of early temporomandibular joint osteoarthritis.
Descriptive values are shown as mean ± SD.Descriptive values are shown as mean ± SD.
Data obtained from repeated measure ANOVA.Data obtained from repeated measures ANOVA.
* P < 0.05, ** P < 0.001 by repeated measure ANOVA. * P < 0.05, ** P < 0.001 by repeated measures ANOVA.
또한, 표 3과 같이 Multivariate linear effect model 분석 결과 과두의 부피 변화량과 25-dihydroxyvitamin D 농도 변화량 사이의 시간 변화에 따른 유의미한 연관 관계가 확인됨에 따라, 모니터링 마커로서의 유효성이 확인되었다. In addition, as shown in Table 3, as a result of multivariate linear effect model analysis, a significant correlation between the volume change of the condyle and the 25-dihydroxyvitamin D concentration change over time was confirmed, confirming the effectiveness as a monitoring marker.
Data obtained from multivariate linear mixed effect model. Data obtained from multivariate linear mixed effect model.
* P < 0.05, ** P < 0.001 by the multivariate linear mixed effect model.* P < 0.05, ** P < 0.001 by the multivariate linear mixed effect model.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Having described specific parts of the present invention in detail above, it is clear to those skilled in the art that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
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