On the mechanism of pharmacological regulation of neoinnervation in the subchondral bone by chondroitin sulfate at late stages of osteoarthritis

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Abstract

BACKGROUND: Today, the molecular mechanisms of pain development and the role of neoinnervation in the articular cartilage (AC) degradation in osteoarthritis (OA) have been revealed.

AIM: Analysis of the mechanism of pharmacological regulation of chondroitin sulfate (CS) neoinnervation in the subchondral bone (SB) at late stages of OA based on a retrospective analysis of the results of an open prospective controlled randomized study of the effectiveness of highly purified CS in parenteral form in individuals with OA of the knee joint (KJ) stage III according to Kellgren-Lawrence and functional insufficiency of the joints of stage II.

MATERIALS AND METHODS: Total knee arthroplasty (TKR) was performed in 67 patients (24 men and 43 women, aged 41 to 73 years) with knee OA in two groups: the control group (CG; n=35) and the main group (MG; n=32). All patients received non-steroidal anti-inflammatory drugs at a standard daily dose upon inclusion in the study. MG patients additionally received a parenteral form of CS, a course of 25 injections for 50 days, 2 months before TKR (according to C. Ranawat). X-ray of the knee was performed. The innervation of the joint tissues was studied using biosamples of the SC, SC, and the joint capsule obtained during TKR: histopathological assessment of the synovial membrane according to GSS, histological assessment, histochemical assessment of the SC according to H. Mankin as modified by V.B. Kraus et al., on the OARSI scale. An enzyme immunoassay was performed on the blood levels at visits 0, 1, and 2: C-reactive protein (CRP), interleukin-6 (IL-6), nerve growth factor β (βNGF), calcitonin gene-related peptide (CGRP), potassium, and calcium.

RESULTS: In patients in the CG, a significant number of capillary loops were found in the AC from the SC side and nerve endings in the AC thickness. In the MG, along with adaptive restructuring, the absence of neoangiogenesis from the SC side and neoinnervation in the AC thickness was shown. At discharge from the hospital and 3 months after TKR, a significant decrease in βNGF, CGRP, VEGF, CRP, IL-6, potassium and calcium in the blood of patients in the MG was recorded.

CONCLUSION: The effectiveness of parenteral HS (Chondroguard®) in relation to OA progression may be due to its effect on neoinnervation and is a new direction in therapeutic targeting of OA.

About the authors

Timur B. Minasov

Bashkir State Medical University; LLC Medical Center “Novomeditsina”

Email: M004@ya.ru
ORCID iD: 0000-0003-1916-3830
SPIN-code: 7865-6011

MD

Russian Federation, Ufa; 74 Socialisticheskaya str., 344002 Rostov-on-Don, Rostov-on-Don region

Irina V. Sarvilina

LLC Medical Center “Novomeditsina”

Author for correspondence.
Email: isarvilina@mail.ru
ORCID iD: 0000-0002-5933-5732
SPIN-code: 7308-6756

MD

Russian Federation, 74 Socialisticheskaya str., 344002 Rostov-on-Don, Rostov-on-Don region

Olga A. Gromova

Federal Research Center “Informatics and Management”

Email: unesco.gromova@gmail.com
ORCID iD: 0000-0002-7663-710X
SPIN-code: 6317-9833

MD

Russian Federation, Moscow

Anton G. Nazarenko

Priorov National Medical Research Center for Traumatology and Orthopedics

Email: NazarenkoAG@cito.priorov.ru
ORCID iD: 0000-0003-1314-2887
SPIN-code: 1402-5186

MD, Dr. Sci. (Medicine), professor RAS

Russian Federation, Moscow

Nikolay V. Zagorodniy

Priorov National Medical Research Center for Traumatology and Orthopedics; Peoples’ Friendship University of Russia named after Patrice Lumumba

Email: zagorodniy@sustav.ru
ORCID iD: 0000-0002-6736-9772
SPIN-code: 6889-8166

MD, Dr. Sci. (Medicine), professor

Russian Federation, Moscow; Moscow

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2. Fig. 1. Neoangiogenesis and neoinnervation in articular cartilage of patients in the control group. Note (here and in Fig. 2): staining with hemotoxylin and eosin; ×125.

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3. Fig. 2. Elements of adaptive restructuring and a uniform line of subchondral bone (a), chondrocytes have a columnar orientation (from 4 to 8 cells in a lacuna; isogenic groups of chondrocytes in the deep zone) (b), capillary loops and nerve endings were not detected in the articular cartilage of patients in the main group.

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4. Fig. 3. Intermolecular interactions of nerve growth factor β (bioinformatics analysis was performed based on the STRING database, version 12.0). Note. NGF — nerve growth factor β, NGFR — nerve growth factor β receptor; NTRK2 — BDNF/NT-3 growth factor receptor; NTRK1 — high-affinity nerve growth factor receptor; NTRK3 — NT-3 growth factor receptor; SORT1 — sortilin; GFRA1 — GDNF family of growth factor alpha 1-receptor; SORCS2 — VPS10 domain-containing receptor SorCS2; GDNF — glial cell-derived neurotrophic factor; NTF4 — neurotrophin-4; TRPA1 — transient receptor potential cation channel, member 1 of subfamily A.

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