Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade

Abstract

ObjectivesWnt16 is implicated in bone fracture and bone mass accrual both in animals and humans. However, its functional roles and molecular mechanism in chondrocyte differentiation and osteoarthritis (OA) pathophysiology remain largely undefined. In this study, we analysed its mechanistic association and functional relationship in OA progression in chondrocyte lineage.MethodsThe role of Wnt16 during skeletal development was examined by Col2a1-Wnt16 transgenic mice and Wnt16fl/fl;Col2a1-Cre (Wnt16-cKO) mice. OA progression was assessed by micro-CT analysis and Osteoarthritis Research Society International score after anterior cruciate ligament transection (ACLT) surgery with Wnt16 manipulation by adenovirus intra-articular injection. The molecular mechanism was investigated in vitro using 3D chondrocyte pellet culture and biochemical analyses. Histological analysis was performed in mouse joints and human cartilage specimens.Results Wnt16 overexpression in chondrocytes in mice significantly inhibited chondrocyte hypertrophy during skeletal development. Wnt16 deficiency exaggerated OA progression, whereas intra-articular injection of Ad-Wnt16 markedly attenuated ACLT-induced OA. Cellular and molecular analyses showed that, instead of β-catenin and calcium pathways, Wnt16 activated the planar cell polarity (PCP) and JNK pathway by interacting mainly with AP2b1, and to a lesser extend Ror2 and CD146, and subsequently induced PTHrP expression through phosphor-Raptor mTORC1 pathway.ConclusionsOur findings indicate that Wnt16 activates PCP/JNK and crosstalks with mTORC1-PTHrP pathway to inhibit chondrocyte hypertrophy. Our preclinical study suggests that Wnt16 may be a potential therapeutic target for OA treatment.

Lessons from joint development for cartilage repair in the clinic

“…17 Tong et al showed that Wnt16 overexpression protected cartilage in a model of osteoarthritis. 44 Wnt16 delayed cartilage breakdown by activating JNK and the WNT planar cell polarity pathway, thereby ultimately up-regulating PTHrP expression. 44…”

“…Further complexity was added by the understanding that while a short burst of WNT activation supports articular cartilage formation and homeostasis, 17,57 excessively prolonged activation resulted in cartilage breakdown. Interestingly, WNT16 is both required and sufficient for cartilage homeostasis following cartilage injury, 17,44 and it is a partial activator of the canonical WNT pathway, maintaining "homeostatic levels" and preventing excessive activation from other more potent ligands. 17,44 The relevance of these findings to human osteoarthritis was confirmed by the association of allelic variants of WNT inhibitory molecules such as FRZB 74 and DOT1L 75 with osteoarthritis.…”

“…Interestingly, WNT16 is both required and sufficient for cartilage homeostasis following cartilage injury, 17,44 and it is a partial activator of the canonical WNT pathway, maintaining "homeostatic levels" and preventing excessive activation from other more potent ligands. 17,44 The relevance of these findings to human osteoarthritis was confirmed by the association of allelic variants of WNT inhibitory molecules such as FRZB 74 and DOT1L 75 with osteoarthritis. These data were replicated in animal models.…”

“…9 Prevents chondrocyte hypertrophy. 44 Buffers activation of β-catenin pathway by stronger canonical WNT ligands. Promotes cartilage homeostasis by maintaining Prg4+ expression, 17 and prevents hypertrophy through regulating mTORC1-PTHrP.…”

BMSCs‐Derived Exosomes Ameliorate Pain Via Abrogation of Aberrant Nerve Invasion in Subchondral Bone in Lumbar Facet Joint Osteoarthritis

“…5,6 Increasing evidence demonstrated that the articular cartilage and subchondral bone acted as a functional unit, and the interplay between them maintains the normal function of LFJ. 7,8 Subchondral bone provides structural support and shock absorber for superficial articular cartilage and undergoes dynamic balance between modeling and remodeling in response to mechanical stress. 9,10 The process of bone remodeling is regulated by osteoclast and osteoblast activity, and abnormal remodeling is believed to trigger the onset of OA.…”