Abstract
There is emerging awareness that subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). This review presents recent investigations on the cellular and molecular mechanism of subchondral bone remodeling, and summarizes the current interventions and potential therapeutic targets related to OA subchondral bone remodeling. The first part of this review covers key cells and molecular mediators involved in subchondral bone remodeling (osteoclasts, osteoblasts, osteocytes, bone extracellular matrix, vascularization, nerve innervation, and related signaling pathways). The second part of this review describes candidate treatments for OA subchondral bone remodeling, including the use of bone-acting reagents and the application of regenerative therapies. Currently available clinical OA therapies and known responses in subchondral bone remodeling are summarized as a basis for the investigation of potential therapeutic mediators.
Highlights
Osteoarthritis (OA) affects all tissues in diarthrodial joints, including articular cartilage, subchondral cortical bone, subchondral trabecular bone, and synovium, and the resultant pathological changes lead to pain, stiffness and dysfunction of the joint
Articular cartilage has an aneural, Subchondral Bone Remodeling in Osteoarthritis avascular, and alymphatic structure composed of 65–80% water, 20–40% extracellular matrix (ECM), and 1–5% chondrocytes
The subchondral bone mesenchymal stem cells (MSCs) therapy was delivered to one knee, while the other knee was treated with either intraarticular MSC injection (n = 60) or total knee arthroplasty (TKA, n = 140) (Table 3, Study 1 and Study 2). These results showed that: (i) precise delivery of MSCs to subchondral bone could postpone TKA in OA patients for more than 10 years; (ii) subchondral bone MSC therapy achieved similar clinical scores as TKA knees in short and long-term follow ups; and (iii) subchondral bone MSC therapy could effectively reduce the size of bone marrow lesions (BMLs) in OA patients, and postpone or prevent the first TKA surgery in young patients with secondary osteonecrosis related to corticosteroids (Table 3, Study 3)
Summary
Osteoarthritis (OA) affects all tissues in diarthrodial joints, including articular cartilage, subchondral cortical bone, subchondral trabecular bone, and synovium, and the resultant pathological changes lead to pain, stiffness and dysfunction of the joint. Administration of the CTSK inhibitor, SB-553484, delayed OA progression in a canine model (Connor et al, 2009) Another novel selective CTSK inhibitor, MIV-711, was recently developed for OA treatment, and showed promising protection against subchondral bone loss (both plate and trabecular bone) and partial alleviation of cartilage deterioration in early OA in rabbit and canine OA models (Lindstrom et al, 2018). Researchers from the same group reported that halofuginone, a natural quinazolinone alkaloid found in the Chinese herb Dichroa febrifuga, showed similar TGFβ1 inhibition effects in OA mouse models (Cui et al, 2016), suggesting that halofuginone may have potential therapeutic effect on regulating subchondral bone in OA Another Chinese herbal extract isolated from the plant Artemisia annua, Artesunate, inhibited subchondral bone TGFβ/Smad signaling pathway and restored the coupled bone remodeling in an ACLT-induced mice OA model (Li et al, 2019) (Table 1).
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