Comparison of angiotensin converting enzyme 1 levels to the grading of knee osteoarthritis

Background and aim. One of the most prevalent chronic joint illnesses is osteoarthritis (OA), which can impair a patient's quality of life by causing joint pain, stiffness, deformity, and narrowed joint spaces. Many factors influence the pathogenesis of Osteoarthritis such as age and body weight, as well as genetic factors that are reported to play a role in the occurrence and progression of Osteoarthritis. Recently, many studies have demonstrated that inflammatory variables contribute to osteoarthritis pathomechanisms. It is currently thought that inflammatory variables alone are an independent risk factor for osteoarthritis. Methods . Observational sub-analysis with a cross-sectional approach to examine the relationship between Angiotensin Converting Enzyme 1 (ACE 1) levels and the grading of osteoarthritis at “Dr. Wahidin Sudirohusodo” Hospital from October 2020 to February 2021. ACE 1 levels were measured using the Elisa KIT and grading of osteoarthritis using the Kellgren and Lawrence criteria. Results . Analysis of the relationship between ACE 1 levels and osteoarthritis grading using the ANOVA test and Post Hoc Bonferonni Test showed a significant relationship between ACE 1 levels and osteoarthritis grading, where high ACE 1 levels were related to osteoarthritis grading. Deficiency and insufficiency (p<0.05). The results of this study are in line with previous research. Conclusion . The higher the ACE 1 level, the more severe the degree of knee osteoarthritis.


INtRoDuCtIoN
Among the most prevalent chronic joint illnesses, osteoarthritis (OA) can result in joint pain, stiffness, deformity, and narrowing of the joint space, all of which have a negative effect on the patient's quality of life [1].Osteoarthritis occurs due to various etiologies resulting in biological and morphological abnormalities [2].Osteoarthritis can affect joints, especially the knee, hand and hip joints [2].
Age, gender, ethnicity, genetics, food, obesity, muscle weakness, excessive physical activity, past trau-ma, reduced proprioceptive function, hereditary variables resulting in osteoarthritis, and mechanical factors are some of the risk factors for osteoarthritis [3].These risk factors affect the development of abnormal bone growth, joint cartilage damage, and bone injury [4].Based on etiology, osteoarthritis can occur primarily (idiopathic) or secondary [4].
The diagnosis of osteoarthritis is based on clinical symptoms.There are no specific supporting examinations that can determine the diagnosis of osteoarthritis [4].Radiological examination can determine the presence of osteoarthritis, but it is not directly related to the clinical symptoms that appear [4].Radiographic assessment of osteoarthritis relies primarily on the assessment of the narrowing of the joint space and osteophytes [5].Osteophytes, namely bone growths at the edges of joints, usually show up earlier than joint space reducing.The primary factors determining the grading of osteoarthritis are joint space constriction and concurrent subchondral bone disease [5].
Genetic and environmental factors influence the pathophysiology of osteoarthritis by activating cellular and molecular pathways that contribute to joint damage [6].Synovial inflammation, oxidative stress, chondrocyte death, cartilage extracellular matrix degradation, subchondral bone sclerosis, and osteophyte production are typical symptoms of affected joints, leading to discomfort, pain, and joint failure [6].In recent years, studies have shown that the main components of RAS, including ACE, AT1R, and AT2R, are expressed in synovial tissue in humans and animals and participate in the pathogenesis of osteoarthritis; their expression levels are related to the degree of inflammation and severity of arthritis [7].
The Renin-Angotensin Aldosterone system influences bone density by participating in the regulation of bone resorption [8].The major RAS proteins and receptors are expressed locally in bone tissue and majorly regulate bone remodeling and metabolism [9].The enzyme Renin transforms angiotensinogen (AGT) into angiotensin I (Ang I), which is subsequently transformed into angiotensin II (Ang II) by Angiotensin Converting Enzyme 1 (ACE 1) [10].Additionally, Ang 2 promotes inflammation and cell proliferation [10].
An essential component of RAS, ACE preserves water, electrolytes, and the internal environment of the organisms balanced [8].By converting Ang 1 into Ang 2, ACE may constrict blood vessels, release aldosterone, and contribute to the inflammatory process of osteoarthritis [7].
On osteoblasts and osteoclasts, angiotensin receptor types 1 and 2 (AT1R and AT2R) are expressed.Furthermore, renin and ACE have also been expressed in bone cells [7].The function of angiotensin II in the skeletal system is to stimulate the proliferation of osteoblast cells in the calvaria via AT1R, apart from that, angiotensin II can also reduce calcium absorption in the bones.Additionally, it has been noted that improving metabolism and bone structure can be achieved by blocking AT1R with losartan [8].

Patient population
The Study population was all patients diagnosed with Osteoarthritis at "Dr.Wahidin Sudirohusodo" Hospital Makassar from October 2020 to February 2021.Samples are individuals who match all criteria for inclusion.

Inclusion and exclusion criteria
The Inclusion criteria: Patients diagnosed with osteoarthritis according to ACR and Kellgren-Lawrence criteria at "Dr.Wahidin Sudirohusodo" Hospital Makassar were then examined for ACE 1 levels.The Exclusion criteria: Participants who could not agree to be part of the study sample, Secondary osteoarthritis patients, and patients who are temporarily taking ACE inhibitor drugs.

Clinical data and sample collection
Sampling was carried out by consecutive sampling.

Statistical analysis
The data was analyzed using SPSS version 25.Statistical tests and descriptive approaches made up the analysis approach.The goal of the cross-sectional design approach, also known as the cross-sectional study, is to gather broad details on the research sample.The mean value, standard deviation (SB), and frequency distribution are calculated using a statistical method.The ANOVA statistical test is employed.If the test p value is less than 0.05, the findings of the statistical test are deemed significant.Complete with tables and figures, the collected results, will be presented narratively.

The relationship between angiotensin converting enzyme levels and the severity of knee osteoarthritis
The relationship between angiotensin converting enzyme levels and the severity of knee osteoarthritis can be seen in Table 3.In this study, to see the relationship between ACE and the severity of knee osteoarthritis, a bivariate analysis using the ANOVA test was carried out, showing a significant relationship between the severity of osteoarthritis and ACE-1 levels (P = 0.048) and it was found that the ACE 1  2).
In subgroup analysis, a significant relationship was found between ACE1 levels and the severity of osteoarthritis grades 1 and 3 (P = 0.016) and grades 1 and 4 (P = 0.044).
This study also found that there was a relationship between BMI and the severity of OA with a P value of (0.002), so we continued to carry out further analysis to assess the relationship between OA and BMI.
A positive association was found between ACE levels and OA grade, with OR 1.019 (1.005-1.033)P = 0.007, and after being corrected for BMI.This relationship remains significant with OR 1.02 (1.006-1.035),P = 0.005 (Figure 2).

DISCuSSIoN
This study examines the relationship between ACE levels and the severity of knee osteoarthritis in Wahidin Sudirohusodo and his network.The 80 research subjects were grouped based on the Kellgren-Lawrence (KL) criteria into groups KL 1 (20 subjects), KL 2 (20 subjects), KL 3 (20 subjects) and KL 4 (20 subjects).All research samples were female.The majority of the sample was aged between 40 -84 years.Body Mass Index is between 44 kg to 99 kg on average.
It is known that ACE-1 changes Angiotensin I to Angiotensin II so that high levels of ACE-1 will cause high levels of Angiotensin II.We know that Angiotensin II is a pro-inflammatory agent which is thought to play a role in increasing the severity of osteoarthritis.
Bivariate analysis using ANOVA test in this study found that A correlation was seen between the severity of knee osteoarthritis and ACE levels, including ACE-1 levels (P = 0.048) and Body Mass Index (P = 0.002), and a non-significant relationship with age (P = 0.991), Waist Circumference (P = 0.548).In accordance with research by Wu et al. (2019) which states that ACE components, Angiotensi I and Angiotensi II, are found in humans synovial tissue, can contribute to the etiology of several inflammatory joint conditions, including osteoarthritis [7].From research by Yan et al. (2017) it is found relationship between increased levels of components of the renin angiotensin system with the severity of inflammation and severity of Osteoathrtitis [11].

Relationship between Grading Osteoatrtitis and BMI
Research by Raud et al. (2020) shows a correlation between increasing body weight and the severity of knee Osteoathrtitis [12].Lee et al. (2012) researched that biomechanical changes are patho-mechanisms that play a role in the relationship between obesity and the incidence and severity of knee OA [13].In this case, there is an increase in the load on the knee joint cartilage which acts as a joint cushion, This results in surface erosion of the joint cartilage and changes the hyaline cartilage's composition, structure, and mechanics [14].
Individuals with a BMI > 30 kg/m 2 have a 6.8 times greater risk of suffering from knee OA compared to normal individuals with a normal BMI [9].The prevalence and severity of knee OA is also associated with obesity [9].A study reported an increase of one level of KL in knee OA sufferers with a BMI > 27.5 kg/m 2 or an increase of > 1.5 mm in joint space narrowing [15].

CoNCLuSIoN
The degree of progression of knee osteoarthritis increases with ACE 1 level.The strength of this study is that it can be considered giving ace inhibitor as a treatment for hypertensive patients with osteoar-thritis.This research has the limitation that ACE 1 levels were measured from blood, so for further research, ACE 1 levels in joint fluid can be examined.

Conflict of interest:
Every author certifies that they have no financial relationships (such as stock ownership, equity holdings, consulting, patent/licensing arrangements, etc.) that could create a conflict of interest about to the work that has been submitted. Ethics

tABLE 5 .
Characteristics of research subjects (N:80)Considering on Table1, the average age found in this study was 63.2 ± 8.84.The mean Body Mass Index found was 27.9 ± 4.72.The mean waist circumference was 100.4 ± 14.7.

tABLE 2 .
The relationship between Angiotensin Converting Enzyme levels and the severity of knee osteoarthritis (N=80) * ANOVA test, significant if P<0.05 FIGuRE 1. Relationship between Angiotensin Converting Enzyme Levels and Severity of Knee Osteoarthritis *Post Hoc Bonferonni Test, significant if P < 0.05 Error Bars: