Abstract

Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However, the mechanisms that initiate subchondral bone angiogenesis remain unclear. We show that abnormally increased platelet-derived growth factor-BB (PDGF-BB) secretion by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to osteoarthritis development. In mice after destabilization of the medial meniscus (DMM), aberrant joint subchondral bone angiogenesis developed during an early stage of osteoarthritis, before articular cartilage damage occurred. Mononuclear preosteoclasts in subchondral bone secrete excessive amounts of PDGF-BB, which activates platelet-derived growth factor receptor-β (PDGFR-β) signaling in pericytes for neo-vessel formation. Selective knockout of PDGF-BB in preosteoclasts attenuates subchondral bone angiogenesis and abrogates joint degeneration and subchondral innervation induced by DMM. Transgenic mice that express PDGF-BB in preosteoclasts recapitulate pathological subchondral bone angiogenesis and develop joint degeneration and subchondral innervation spontaneously. Our study provides the first evidence to our knowledge that PDGF-BB derived from preosteoclasts is a key driver of pathological subchondral bone angiogenesis during osteoarthritis development and offers a new avenue for developing early treatments for this disease.

Highlights

  • Osteoarthritis is the most prevalent chronic joint disease affecting knees, hands, hips, and spine; it is one of the leading musculoskeletal causes of impaired mobility [1,2,3]

  • We previously revealed that bone/bone marrow mononuclear preosteoclasts, i.e., TRAP+ preosteoclasts, can secrete platelet-derived growth factor–BB (PDGF-BB), which is essential for angiogenesis with coupled osteogenesis to maintain bone homeostasis in healthy mice [46]

  • Using destabilization of the medial meniscus (DMM) osteoarthritis mouse models, we found that mononuclear preosteoclasts in subchondral bone/bone marrow of osteoarthritic joints are stimulated very early in mice after DMM surgery and produce a markedly high amount of PDGF-BB, which activates platelet-derived growth factor receptor–β (PDGFR-β) signaling to stimulate aberrant development of subchondral bone angiogenesis with coupled osteogenesis as well as nerve ingrowth

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Summary

Introduction

Osteoarthritis is the most prevalent chronic joint disease affecting knees, hands, hips, and spine; it is one of the leading musculoskeletal causes of impaired mobility [1,2,3]. No effective disease-modifying drug is available to treat osteoarthritis [4,5,6] mainly because of the limited understanding of the mechanisms that drive the pathological process at the initiation stage. Osteoarthritis is characterized by progressive degeneration of articular cartilage (AC), structural alterations of subchondral bone, osteophyte formation, and synovial inflammation [3, 7, 8]. AC degeneration, the primary concern in osteoarthritis that leads to joint pain and dysfunction, was initially thought to be the only factor driving osteoarthritis development [9,10,11]. Recent evidence suggests that pathological alterations in subchondral bone contribute to osteoarthritis development [15,16,17,18,19,20,21,22,23]

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