Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

Qin, Lei; Fu, Xuekun; Ma, Jing; Lin, Manxia; Zhang, Peijun; Wang, Yishu; Yan, Qinnan; Tao, Chu; Liu, Wen; Tang, Bin; Chen, Di; Bai, Xiaochun; Cao, Huiling; Xiao, Guozhi

doi:10.1038/s42003-021-01950-4

Cited by 24 publications

(27 citation statements)

References 89 publications

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“…Interestingly, our previous study has shown that deletion of Kindlin-2 in Dmp1-expressing mature osteoblasts and osteocytes causes decreased bone mass and abnormal bone remodeling by reducing osteoblast but increasing osteoclast formation and function [ 22 ]. We further demonstrate that Kindlin-2 in osteocytes can modulate PTH1R signaling and mediate mechanotransduction to regulate bone mass and homeostasis [ 23 , 25 ]. Thus, results from this study and our previous studies provide an integrated view on the roles of Kindlin-2 expression in osteoblastic lineage cells in regulation of bone mass accrual and homeostasis in mice.…”

Section: Discussionmentioning

confidence: 99%

“…In mammalian cells, Kindlin family proteins have three members, i.e., Kindlin- 1, -2 and -3, encoded by genes Fermt1 , Fermt2 and Fermt3 , respectively [ [18] , [19] , [20] ]. Kindlin-2 has been reported to be involved in regulation of the development and homeostasis of multiple organs and tissues, including skeleton, kidney, heart, pancreas, adipose tissue, small intestine testicle, and neural system, through both integrin-dependent and integrin-independent mechanisms [ [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] ]. For example, Kindlin-2 expression in Prx1-expressing mesenchymal progenitors is essential for mesenchymal cell differentiation and early skeletal development [ 21 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

“…For example, Kindlin-2 expression in Prx1-expressing mesenchymal progenitors is essential for mesenchymal cell differentiation and early skeletal development [ 21 , 37 ]. Furthermore, Kindlin-2 modulates bone remodelling by control of expression of sclerostin and receptor activator of nuclear factor-κ B ligand (Rankl) in osteocytes [ 22 , 23 , 25 ]. However, whether and how Kindlin-2 plays a role in osteoprogenitors remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice

Gong

et al. 2022

Journal of Orthopaedic Translation

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Background Our recent studies demonstrate that the focal adhesion protein Kindlin-2 exerts crucial functions in the mesenchymal stem cells, mature osteoblasts and osteocytes in control of early skeletal development and bone homeostasis in mice. However, whether Kindlin-2 plays a role in osteoprogenitors remains unclear. Materials and methods Mice lacking Kindlin-2 expression in osterix (Osx)-expressing cells (i.e., osteoprogenitors) were generated. Micro-computerized tomography (μCT) analyses, histology, bone histomorphometry and immunohistochemistry were performed to determine the effects of Kindlin-2 deletion on skeletal development and bone mass accrual and homeostasis. Bone marrow stromal cells (BMSCs) from mutant mice ( Kindlin-2 fl/fl ; Osx Cre ) and control littermates were isolated and determined for their osteoblastic differentiation capacity. Results Kindlin-2 was highly expressed in osteoprogenitors during endochondral ossification. Deleting Kindlin-2 expression in osteoprogenitors impaired both intramembranous and endochondral ossifications. Mutant mice displayed multiple severe skeletal abnormalities, including unmineralized fontanel, limb shortening and growth retardation. Deletion of Kindlin-2 in osteoprogenitors impaired the growth plate development and largely delayed formation of the secondary ossification center in the long bones. Furthermore, adult mutant mice displayed a severe low-turnover osteopenia with a dramatic decrease in bone formation which exceeded that in bone resorption. Primary BMSCs isolated from mutant mice exhibited decreased osteoblastic differentiation capacity. Conclusions Our study demonstrates an essential role of Kinlind-2 expression in osteoprogenitors in regulating skeletogenesis and bone mass accrual and homeostasis in mice. The translational potential of this article This study reveals that Kindlin-2 through its expression in osteoprogenitor cells controls chondrogenesis and bone mass. We may define a novel therapeutic target for treatment of skeletal diseases, such as chondrodysplasia and osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice

Gong

et al. 2022

Journal of Orthopaedic Translation

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“…Disruption of microtubules resulted in a blunted decrease in sclerostin expression upon mechanical loading [ 76 ]. Similarly, Kindlin-2, a protein responsible for cytoskeleton organization and the formation of focal adhesions, was essential to the suppression of sclerostin expression through inhibiting Smad2/3 signaling [ 77 ]. These findings again confirm the role of the cytoskeleton in mechanical sensing.…”

Section: Osteocyte Dysfunctionmentioning

confidence: 99%

Osteocyte Dysfunction in Joint Homeostasis and Osteoarthritis

Zhang

Wen

2021

IJMS

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Structural disturbances of the subchondral bone are a hallmark of osteoarthritis (OA), including sclerotic changes, cystic lesions, and osteophyte formation. Osteocytes act as mechanosensory units for the micro-cracks in response to mechanical loading. Once stimulated, osteocytes initiate the reparative process by recruiting bone-resorbing cells and bone-forming cells to maintain bone homeostasis. Osteocyte-expressed sclerostin is known as a negative regulator of bone formation through Wnt signaling and the RANKL pathway. In this review, we will summarize current understandings of osteocytes at the crossroad of allometry and mechanobiology to exploit the relationship between osteocyte morphology and function in the context of joint aging and osteoarthritis. We also aimed to summarize the osteocyte dysfunction and its link with structural and functional disturbances of the osteoarthritic subchondral bone at the molecular level. Compared with normal bones, the osteoarthritic subchondral bone is characterized by a higher bone volume fraction, a larger trabecular bone number in the load-bearing region, and an increase in thickness of pre-existing trabeculae. This may relate to the aberrant expressions of sclerostin, periostin, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, insulin-like growth factor 1, and transforming growth factor-beta, among others. The number of osteocyte lacunae embedded in OA bone is also significantly higher, yet the volume of individual lacuna is relatively smaller, which could suggest abnormal metabolism in association with allometry. The remarkably lower percentage of sclerostin-positive osteocytes, together with clustering of Runx-2 positive pre-osteoblasts, may suggest altered regulation of osteoblast differentiation and osteoblast-osteocyte transformation affected by both signaling molecules and the extracellular matrix. Aberrant osteocyte morphology and function, along with anomalies in molecular signaling mechanisms, might explain in part, if not all, the pre-osteoblast clustering and the uncoupled bone remodeling in OA subchondral bone.

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“…Recently, increasing attention has been paid to its roles in control of organogenesis and homeostasis through both integrin-dependent and integrin-independent mechanisms (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). We recently demonstrate that Kindlin-2 plays critical roles in regulation of skeletal development and bone remodeling through distinct molecular mechanisms (41)(42)(43)(44). However, it is not known whether Kindlin-2 has a role in articular cartilage homeostasis and whether alterations in its expression in articular chondrocytes are involved in OA initiation and progression.…”

Section: Introductionmentioning

confidence: 99%

Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis

Lai

Chen

et al. 2021

Preprint

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Osteoarthritis (OA) is an aging-related degenerative joint disease, which has no cure partly due to limited understanding of its pathological mechanism(s). Here we report that the focal adhesion protein Kindlin-2, but not Kindlin-1 or -3, is highly expressed in articular chondrocytes of the hyaline cartilage, which is dramatically decreased in the degenerated articular cartilage of aged mice and patients with OA. Inducible deletion of Kindlin-2 in chondrocytes at adult stage leads to spontaneous OA and much severe OA lesions in the mice receiving the surgery of destabilization of the medial meniscus. Mechanistically, Kindlin-2 deficiency promotes mitochondrial oxidative stress and activates Stat3 in articular chondrocytes, leading to Runx2-mediated chondrocyte hypertrophic differentiation and catabolism. In vivo, systemic pharmacological blockade of Stat3 activation or genetic ablation of Stat3 in chondrocytes reverses aberrant accumulation of Runx2 and ECM-degrading enzymes and limits OA deteriorations caused by Kindlin-2 deficiency. Furthermore, genetic inactivation of Runx2 in chondrocytes reverses structural changes and OA lesions caused by Kindlin-2 deletion without down-regulating p-Stat3 in articular chondrocytes. Of translational significance, intraarticular injection of Kindlin-2-expressing adeno-associated virus decelerates progression of aging- and instability-induced knee joint OA in mice. Collectively, we identify a novel pathway comprising of Kindlin-2, Stat3 and Runx2 in articular chondrocytes responsible for maintaining integrity of the articular cartilage and define a potential therapeutic target for OA.

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Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

Cited by 24 publications

References 89 publications

Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice

Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice

Osteocyte Dysfunction in Joint Homeostasis and Osteoarthritis

Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis

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