Parathyroid hormone attenuates osteoarthritis pain by remodeling subchondral bone in mice

Sun, Qi; Zhen, Gehua; Li, Tuo Peter; Guo, Qiaoyue; Li, Yusheng; Su, Weiping; Xue, Peng; Wang, Xiao; Wan, Mei; Guan, Yun; Dong, Xinzhong; Li, Shaohua; Cai, Ming; Cao, Xu

doi:10.7554/elife.66532

Cited by 46 publications

(40 citation statements)

References 71 publications

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“…Our findings show that humans and mice with MetS-OA have a subchondral bone phenotype distinct from that of PTOA and have a greater likelihood of developing osteoarthritis-related subchondral bone damage. Structurally, contrary to the increased osteoclast bone resorption in subchondral bone in early-stage PTOA (30,60,61), there is rapid thickening of subchondral bone plate and trabecular bone in HFD-challenged mice and STR/Ort mice, both of which are MetS-OA mouse models. These subchondral alterations appear much earlier than the occurrence of cartilage degradation.…”

Section: Discussionmentioning

confidence: 94%

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

Wan

Liu

et al. 2022

Preprint

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Background: Metabolic syndrome–associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA. Methods: Analysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system. Results: Humans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal anti-inflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA. Conclusions: Our findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential. Funding: This work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to M.W., R01AR079620 to S.D., and P01AG066603 to X.C.

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Section: Discussionmentioning

confidence: 94%

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

Wan

Liu

et al. 2022

Preprint

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“… 28 PTH-mediated restriction of TGFβ signalling is based on which PTH can engage TβRII in a complex with PTH1R. 29 Accordingly, the PTH1R–TβRII complex induced the accretion of cAMP, activation of CREB transcriptional activity. 30 PTH (1–34) is a complete, bioactive PTH group that regulates blood calcium and bone metabolism and is currently used as a synthetic drug in the treatment of osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

PTHrP promotes subchondral bone formation in TMJ-OA

Zhang

Zhou

et al. 2022

Int J Oral Sci

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PTH-related peptide (PTHrP) improves the bone marrow micro-environment to activate the bone-remodelling, but the coordinated regulation of PTHrP and transforming growth factor-β (TGFβ) signalling in TMJ-OA remains incompletely understood. We used disordered occlusion to establish model animals that recapitulate the ordinary clinical aetiology of TMJ-OA. Immunohistochemical and histological analyses revealed condylar fibrocartilage degeneration in model animals following disordered occlusion. TMJ-OA model animals administered intermittent PTHrP (iPTH) exhibited significantly decreased condylar cartilage degeneration. Micro-CT, histomorphometry, and Western Blot analyses disclosed that iPTH promoted subchondral bone formation in the TMJ-OA model animals. In addition, iPTH increased the number of osterix (OSX)-positive cells and osteocalcin (OCN)-positive cells in the subchondral bone marrow cavity. However, the number of osteoclasts was also increased by iPTH, indicating that subchondral bone volume increase was mainly due to the iPTH-mediated increase in the bone-formation ability of condylar subchondral bone. In vitro, PTHrP treatment increased condylar subchondral bone marrow-derived mesenchymal stem cell (SMSC) osteoblastic differentiation potential and upregulated the gene and protein expression of key regulators of osteogenesis. Furthermore, we found that PTHrP-PTH1R signalling inhibits TGFβ signalling during osteoblastic differentiation. Collectively, these data suggested that iPTH improves OA lesions by enhancing osteoblastic differentiation in subchondral bone and suppressing aberrant active TGFβ signalling. These findings indicated that PTHrP, which targets the TGFβ signalling pathway, may be an effective biological reagent to prevent and treat TMJ-OA in the clinic.

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“… 99 Additionally, intermittent parathyroid hormone treatment attenuates OA pain in a DMM model, in association with inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration. 100 A phase-2 study is currently ongoing to evaluate the efficacy of PTH in knee OA participants (NCT03072147).…”

Section: Bone-driven Endotypementioning

confidence: 99%

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

Oo¹,

Little²,

Duong³

et al. 2021

DDDT

113

163

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Osteoarthritis (OA) is a complex heterogeneous articular disease with multiple joint tissue involvement of varying severity and no regulatory-agency-approved diseasemodifying drugs (DMOADs). In this review, we discuss the reasons necessitating the development of DMOADs for OA management, the classifications of clinical phenotypes or molecular/mechanistic endotypes from the viewpoint of targeted drug discovery, and then summarize the efficacy and safety profile of a range of targeted drugs in Phase 2 and 3 clinical trials directed to cartilage-driven, bone-driven, and inflammation-driven endotypes. Finally, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers.

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Parathyroid hormone attenuates osteoarthritis pain by remodeling subchondral bone in mice

Cited by 46 publications

References 71 publications

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome-Associated Osteoarthritis through Cyclooxygenase 2

PTHrP promotes subchondral bone formation in TMJ-OA

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

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