Positive-Feedback Regulation of Subchondral H-Type Vessel Formation by Chondrocyte Promotes Osteoarthritis Development in Mice

Abstract

Vascular-invasion-mediated interactions between activated articular chondrocytes and subchondral bone are essential for osteoarthritis (OA) development. Here, we determined the role of nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling in the crosstalk across the bone cartilage interface and its regulatory mechanisms. Then mice with chondrocyte-specific mTORC1 activation (Tsc1 CKO and Tsc1 CKO ) or inhibition (Raptor CKO ) and their littermate controls were subjected to OA induced by destabilization of the medial meniscus (DMM) or not. DMM or Tsc1 CKO mice were treated with bevacizumab, a vascular endothelial growth factor (VEGF)-A antibody that blocks angiogenesis. Articular cartilage degeneration was evaluated using the Osteoarthritis Research Society International score. Immunostaining and Western blotting were conducted to detect H-type vessels and protein levels in mice. Primary chondrocytes from mutant mice and ADTC5 cells were treated with interleukin-1β to investigate the role of chondrocyte mTORC1 in VEGF-A secretion and in vitro vascular formation. Clearly, H-type vessels were increased in subchondral bone in DMM-induced OA and aged mice. Cartilage mTORC1 activation stimulated VEGF-A production in articular chondrocyte and H-type vessel formation in subchondral bone. Chondrocyte mTORC1 promoted OA partially through formation of VEGF-A-stimulated subchondral H-type vessels. In particular, vascular-derived nutrients activated chondrocyte mTORC1, and stimulated chondrocyte activation and production of VEGF, resulting in further angiogenesis in subchondral bone. Thus a positive-feedback regulation of H-type vessel formation in subchondral bone by articular chondrocyte nutrient-sensing mTORC1 signaling is essential for the pathogenesis and progression of OA. © 2018 American Society for Bone and Mineral Research.

Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development

“…Angiogenesis in cartilage was observed only at a later stage, when structural damage of AC developed (Figure 7). Our results, in agreement with the findings of several previous studies, suggest that neo-vessel formation in subchondral bone is characterized by the development of osteogenesis-coupling type H vessels (CD31 hi Emcn hi ) (32,34,35,56). The simultaneous increase in osteogenesis and subchondral bone microarchitecture alterations that we observed in osteoarthritic mice further support this assumption.…”

“…The increased LRG1 in subchondral bone was detected at 30 days after ACLT surgery, when AC degeneration had already occurred (16,34), suggesting that LRG1 may regulate subchondral bone angiogenesis at a relatively late stage of posttraumatic osteoarthritis. A recent study by Lu et al, using the DMM OA mouse model, demonstrated that activated mTOR complex 1 in the hypertrophic chondrocytes in AC mediated the production of VEGF from the chondrocytes, resulting in subchondral bone angiogenesis at 5 weeks after DMM surgery (32). During new vessel growth and remodeling, the concentration and activity of angiogenesis factors in the local environment must be controlled and coordinated precisely to induce formation and stabilization of new vessels (58).…”

“…This osteochondral angiogenesis not only stimulates early osteophyte development and ossification in the cartilage but also causes innervation of AC, causing joint pain. Consistently, animal studies have shown that aberrant subchondral bone angiogenesis coupled with osteogenesis may contribute to the development of subchondral bone marrow lesions, increased subchondral bone plate thickness, and eventual AC damage (16,(32)(33)(34)(35). However, the key factor(s) for the development of pathological subchondral bone angiogenesis and the main source of the factor(s) during osteoarthritis development remain unclear.…”

Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2

“…Our previous study demonstrated the key role of the chondrocyte mTORC1 pathway in regulating cell proliferation and differentiation in OA 29. We also found that chondrocyte mTORC1 promoted OA partially through formation of vascular endothelial growth factor-A-stimulated subchondral H-type vessels 43. The current study demonstrates an important role of macrophage mTORC1 in OA synovitis.…”

Motivating role of type H vessels in bone regeneration

“…In addition, mTORC1 activation in cartilage stimulated VEGF‐A production in articular chondrocytes and type H vessel formation in subchondral bone. Mechanistic target of rapamycin complex (mTORC) in chondrocytes promoted osteoarthritis partially through formation of VEGF‐A‐stimulated subchondral type H vessels 104 . Moreover, type H EC‐derived Mmp‐9 has crucial roles in cartilage matrix invasion and promotion of bone formation 105 .…”