24R,25-Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats.

Barbara D Boyan,Richard D Coutts,Qingfen Pan,Zvi Schwartz,Sharon L Hyzy,Robert Healey,Kayla M Scott,Sudha Agarwal

doi:10.1371/journal.pone.0161782

Abstract

Osteoarthritis (OA) in humans is associated with low circulating 25-hydroxyvitamin D3 [25(OH)D3]. In vitamin D replete rats, radiolabeled 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] accumulates in articular cartilage following injection of [3H]-25(OH)D3. Previously, we showed that 24R,25(OH)2D3 blocks chondrocyte apoptosis via phospholipase D and p53, suggesting a role for 24R,25(OH)2D3 in maintaining cartilage health. We examined the ability of 24R,25(OH)2D3 to prevent degenerative changes in articular cartilage in an OA-like environment and the potential mechanisms involved. In vitro, rat articular chondrocytes were treated with IL-1β with and without 24R,25(OH)2D3 or 1α,25(OH)2D3. 24R,25(OH)2D3 but not 1α,25(OH)2D3 blocked the effects of IL-1β in a dose-dependent manner, and its effect was partially mediated through the TGF-β1 signaling pathway. In vivo, unilateral anterior cruciate ligament transections were performed in immunocompetent rats followed by intra-articular injections of 24R,25(OH)2D3 or vehicle (t = 0, 7, 14, 21 days). Tissues were harvested on day 28. Joints treated with vehicle had changes typical of OA whereas joints treated with 24R,25(OH)2D3 had less articular cartilage damage and levels of inflammatory mediators. These results indicate that 24R,25(OH)2D3 protects against OA, and suggest that it may be a therapeutic approach for preventing trauma-induced osteoarthritis.

Highlights

Osteoarthritis (OA) is a degenerative condition that affects 12.1% of the US population over the age of 25 [1] and is the leading cause of disability in the elderly [2]
In a preliminary set of experiments, we examined whether it would be possible to passage the rat articular chondrocytes to increase the number of cells and reduce the need for primary cultures
The addition of IL-1β caused a dose-dependent increase in nitric oxide production (Fig 1A), matrix metalloproteinases (MMPs)-13 activity (Fig 1B), and Prostaglandin E2 (PGE2) production (Fig 1C)

Summary

Introduction

Osteoarthritis (OA) is a degenerative condition that affects 12.1% of the US population over the age of 25 [1] and is the leading cause of disability in the elderly [2]. It is characterized by PLOS ONE | DOI:10.1371/journal.pone.0161782. During the development of OA, the bone underlying the articular cartilage becomes hypermineralized and stiffer [5], altering the mechanical properties of the joint and the transport of nutrients into the cartilage tissue from the bone vasculature and marrow [6]. The synovial fluid within the joint space exhibits altered chemistry, including increased content of inflammatory cytokines and products of cartilage matrix breakdown [7]. The synovium, which is an innervated tissue, shows changes [8], suggesting that it is responsible for the pain associated with OA in addition to being a source of inflammatory cytokines

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