Osteocytes and mechanical loading: The Wnt connection

Bullock, Whitney A.; Pavalko, Fredrick M.

doi:10.1111/ocr.12282

Cited by 24 publications

(17 citation statements)

References 21 publications

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“…Wnt signaling plays a vital role in skeletal health, mainly via osteogenic differentiation of precursor cells, osteocyte viability, and osteocyte signaling to other bone cells ( 43 , 44 ). Wnt/β-catenin activation in osteocytes mainly contributes to the anabolic effect in bone ( 45 ).…”

Section: Introductionmentioning

confidence: 99%

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

2020

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Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.

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Section: Introductionmentioning

confidence: 99%

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

2020

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“…Wnt/β-catenin signaling response to mechanical loading is critical for bone homeostasis [21,45], and it is also reported to promote osteogenesis and inhibit adipogenesis [46]. Wnt/β-catenin signaling is a primary fate regulator of adipocytes and osteoblasts, whereby an accumulation of β-catenin was associated with a dose-dependent increase in osteogenesis and a decrease in adipocyte differentiation [47].…”

Section: Discussionmentioning

confidence: 99%

Mechanical Loading Prevents Obesity-Associated Bone Loss by Maintaining the Balance between Adipocytes and Osteoblasts

Liu

et al. 2020

Preprint

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Background: Globally increasing obesity is closely linked to bone homeostasis. Maintaining the balance between differentiate of adipocytes and osteoblasts from bone marrow mesenchymal stem cells (BMSCs) is important for bone homeostasis. While mechanical loading has been shown to improve bone remodeling by promoting osteoblast differentiation, little is known about its effects on obesity-associated bone loss. Methods: Using obese mice induced by high-fat diet and ovariectomy (OVX), the effects of mechanical loading in a form of knee loading (1 N, 5 Hz, 6 min/day) was applied with for 4 weeks. The mice were sorted into five groups: standard diet control (SC), high-fat diet control (HF), HF and loading (HFL), HF and ovariectomy (HO), and HO and loading (HOL). Femurs were harvested for histomorphometry analysis. Bone marrow-derived cells were isolated to examine the banlance between differentiation of adipocytes and osteoblasts. Immunohistochemical analyses and Western blotting analyses were performed to evaluate markers for adipocytes, osteoblasts, and Wnt signaling.Results: High-fat diet presented higher body weight, body fat, and body mass index (BMI), as well as bone loss than standard diet, and the detrimental changes in OVX mice were even higher. The daily application of knee loading significantly decreased BMI, the numbers and perimeter of adipocytes, and the differentiation of adipocytes. The expression of C/EBPα and PPARγ were suppressed by knee loading. The loaded group also presented a significant increase in bone mineral density and contents, and the circumference of trabecular bone. Regarding osteoblasts, knee loading enhanced the number of osteoblasts on bone surface, differentiation of osteoblasts, and the level of Runx2 and ALP. Furthermore, Wnt signaling involved in the effect of knee loading on attenuating obesity-induced bone loss. Conclusions: This study supported evidence that knee loading offers a new therapeutic option to prevent obesity-related bone loss by altering the balance between adipocytes and osteoblasts in the bone marrow, and the effect is associated with Wnt signaling.

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“…[ 36 , 37 ] Recent evidence has indicated that modulation of sclerostin levels, via activation of the Piezo1-Akt pathway and inhibition of Wnt/LRP5 and TSC1/mTORC1 signaling, appears to finely tune the regional and local osteogenesis coordinated by osteocytes in response to increased mechanical stimulation. [ 11 – 14 , 38 ] In addition, the expression of sclerostin increased when mechanical loading decreased and reduced when mechanical loading increased [Figure 2 ]. [ 38 – 40 ] Therefore, sclerostin modulation seems to be a target to develop the effect of orthodontic treatment.…”

Section: Sclerostin In Tooth Movementmentioning

confidence: 99%

“…[ 8 – 10 ] This suggests that the loss of sclerostin has a positive impact in periodontitis progression. Meanwhile, current research has shown that the expression of sclerostin is influenced by mechanical force stimulation [ 11 – 14 ] ; thus, sometimes, periodontitis can be induced during orthodontic treatment. [ 15 ] Further, orthodontic tooth movement has been demonstrated as biological bone remodeling induced by mechanical force.…”

Section: Introductionmentioning

confidence: 99%

Sclerostin regulation: a promising therapy for periodontitis by modulating alveolar bone

Wang²,

Li³

et al. 2020

Chinese Medical Journal

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Periodontitis is one of the most prevalent epidemics affecting human health and life recently, and exploration of the pathogenesis and treatment of periodontitis has been valued by scholars. In recent years, sclerostin, a new factor on bone resorption and reconstruction caused by inflammation and mechanical stimulation, has been a research hotspot. This article summarizes the researches on sclerostin in periodontitis development in recent years. Among them, sclerostin has been shown to be a critical negative regulator of bone formation, thereby inhibiting bone remodeling in periodontitis development, and is closely associated with tooth movement. Besides, evidence indicates that the removal of sclerostin seems to reasonably protect the alveolar bone from resorption. Regulation of sclerostin expression is a novel, promising treatment for periodontitis and addresses several complications seen with traditional therapies; accordingly, many drugs with similar mechanisms have emerged. Moreover, the application prospect of sclerostin in periodontal therapy combined with orthodontic treatment is another promising approach. There are also a lot of drugs that regulate sclerostin. Anti-sclerostin antibody (Scl-Ab) is the most direct one that inhibits bone resorption caused by sclerostin. At present, drugs that inhibit the expression of sclerostin have been applied to the treatment of diseases such as multiple myeloma and osteoporosis. Therefore, the application of sclerostin in the oral field is just around the corner, which provides a new therapeutic bone regulation strategy in oral and general health.

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Osteocytes and mechanical loading: The Wnt connection

Cited by 24 publications

References 21 publications

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

Mechanical Loading Prevents Obesity-Associated Bone Loss by Maintaining the Balance between Adipocytes and Osteoblasts

Sclerostin regulation: a promising therapy for periodontitis by modulating alveolar bone

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