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Review
. 2021 Jan 21:8:607764.
doi: 10.3389/fcell.2020.607764. eCollection 2020.

Subchondral Bone Remodeling: A Therapeutic Target for Osteoarthritis

Xiaobo Zhu  1   2 , Yau Tsz Chan  1   3 , Patrick S H Yung  1   2 , Rocky S Tuan  1   3 , Yangzi Jiang  1   3
Affiliations
Review

Subchondral Bone Remodeling: A Therapeutic Target for Osteoarthritis

Xiaobo Zhu et al. Front Cell Dev Biol. .

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.

Keywords: cellular and molecular targets; osteoarthritis; regenerative therapy; stem cells; subchondral bone; subchondral bone remodeling.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Alterations of subchondral bone during OA progression. (A) Located at the ends of bones, articular cartilage provides a low friction surface for weight bearing and joint movement, and is made up of four zones: superficial zone, middle zone, deep zone, and calcified zone. In the healthy joint, the thin layer of calcified zone/cartilage (yellow) present at the bottom of the articular cartilage is separated from the upper three zones by the histological marker termed tidemark. Subchondral bone is the bone tissue lying beneath the calcified cartilage, and includes both the subchondral cortical plate and subchondral trabecular bone, although there is no precise distinction for the differences between these two structures. (Inset) Depiction of the mineralized rod and plate structures in the trabecular bone. (B) In early OA, when the cartilage is still intact, the thickness of subchondral cortical plate is decreased due to elevated rate of bone remodeling. At the same time, bone loss also occurs in the subchondral trabecular bone. (Inset) A drastic loss of rod-like trabeculae and mild thickening of plate-like trabeculae is also detected in early OA. (C) In late OA, when degenerative changes are evident in articular cartilage, the thickness of the subchondral plate is increased, and the subchondral trabecular bone becomes sclerotic. Other periarticular bone changes, such as the formation of osteophytes (blue arrows) also occurs at this stage. The amount of calcified cartilage expands and penetrates into the upper hyaline articular cartilage, with the tidemark duplicated or disrupted. (Inset) The drastic loss of rod-like trabeculae and thickening of plate-like trabeculae continue in late OA. Inset figures depicting structure of trabecular plate and rod are reprinted with permission from Chen et al. (2018).
Figure 2
Figure 2
Cellular targets in subchondral bone remodeling. (A) Subchondral bone remodeling in OA (as illustrated in the knee). Cells and cellular structures depicted include MSCs (B), osteoclasts (C), osteoblasts (D), osteocytes (E), and blood vessels and nerves (F). Increased osteoclast-mediated subchondral bone resorption (depicted by the large lacuna formed) at the onset of OA results in the release of growth factors previously embedded in bone ECM into the subchondral bone marrow. Subsequent actions of these factors, such as TGFβ contribute to angiogenesis, nerve innervation, and recruitment of MSCs and osteoprogenitors. These cellular processes together lead to activated bone formation, uncoupled bone remodeling, and disruption of the subchondral bone architecture. These alterations in the subchondral bone impair its mechanical properties of subchondral bone, such as load dissipation, and contribute to degeneration of articular cartilage. Current therapeutics, potential targets and potential therapies for subchondral bone remodeling are shown for: (B) MSCs, (C) osteoclasts, (D) osteoblasts, (E) osteocytes, and (F) blood vessels and nerves.
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