Low bone mass resulting from impaired estrogen signaling in bone increases severity of load-induced osteoarthritis in female mice

Ziemian, Sophia N.; Ayobami, Olufunmilayo O.; Rooney, Amanda M.; Kelly, Natalie H.; Holyoak, Derek T.; Ross, F. Patrick; Meulen, Marjolein C. H. van der

doi:10.1016/j.bone.2021.116071

Cited by 16 publications

(17 citation statements)

References 61 publications

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“… 11 After applying cyclic mechanical loading to female osteoblast-specific-ERα-knockout (pOC-ERαKO) mice, Ziemian et al found that the pOC-ERαKO mice developed more severe cartilage damage, larger osteophytes, and greater joint capsule fibrosis than the littermate controls, suggesting that loss of ERα in subchondral bone may be a potential mechanism of OA pathology. 100 Engdahl et al investigated the role of estrogen and ERα in a rheumatoid arthritis animal model established with cartilage-specific knockout (Col2a1-ERαKO) mice. They used antigen-induced arthritis to establish the model and analyzed knee joint synovitis and cartilage destruction.…”

Section: Role Of Erα In Regulating Chondrocyte Phenotype and Response...mentioning

confidence: 99%

Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α

Wang

Rothrauff

et al. 2023

Bone Res

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In the synovial joint, mechanical force creates an important signal that influences chondrocyte behavior. The conversion of mechanical signals into biochemical cues relies on different elements in mechanotransduction pathways and culminates in changes in chondrocyte phenotype and extracellular matrix composition/structure. Recently, several mechanosensors, the first responders to mechanical force, have been discovered. However, we still have limited knowledge about the downstream molecules that enact alterations in the gene expression profile during mechanotransduction signaling. Recently, estrogen receptor α (ERα) has been shown to modulate the chondrocyte response to mechanical loading through a ligand-independent mechanism, in line with previous research showing that ERα exerts important mechanotransduction effects on other cell types, such as osteoblasts. In consideration of these recent discoveries, the goal of this review is to position ERα into the mechanotransduction pathways known to date. Specifically, we first summarize our most recent understanding of the mechanotransduction pathways in chondrocytes on the basis of three categories of actors, namely mechanosensors, mechanotransducers, and mechanoimpactors. Then, the specific roles played by ERα in mediating the chondrocyte response to mechanical loading are discussed, and the potential interactions of ERα with other molecules in mechanotransduction pathways are explored. Finally, we propose several future research directions that may advance our understanding of the roles played by ERα in mediating biomechanical cues under physiological and pathological conditions.

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Section: Role Of Erα In Regulating Chondrocyte Phenotype and Response...mentioning

confidence: 99%

Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α

Wang

Rothrauff

et al. 2023

Bone Res

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“…47 ACL transection resulted in impaired locomotion, mechanical allodynia, and mechanical loading loss in the early phase in animal studies. 40,46 ACLT and sham surgery decreased the weightbearing and increased the number of TRAP-positive osteoclasts in the subchondral bone as early as 1 week. 43 The activation of osteoclasts promoted proinflammatory cytokines and proteases, contributing to cartilage damage.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, subchondral bone osteopenia induced by ACLT or osteoporosis could be a risk factor of OA pathology. 10,46 Subchondral bone osteopenia would reduce subchondral bone stiffness, causing osteochondral deformation during cyclic loading, altering stresses transmitted to cartilage and eventually leading to increased cartilage degeneration. 46 The study had several limitations.…”

Section: Discussionmentioning

confidence: 99%

Axial Compressive Loading Attenuates Early Osteoarthritis by Reducing Subchondral Bone Remodeling

Pan

et al. 2023

Am J Sports Med

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Background: Mechanical loading and alendronate (ALN) can be used as noninvasive physical therapy methods for osteoarthritis (OA). However, the timing and efficacy for treatments are unknown. Purpose: To determine whether the timing of mechanical loading and ALN influences the pathobiological changes of OA. Study Design: Controlled laboratory study. Methods: Mice with OA induced by anterior cruciate ligament transection were subjected to early (1-3 weeks) or late (5-7 weeks) axial compressive dynamic load or intraperitoneal injection of ALN. Changes in gait were analyzed using gait analysis system, pathobiological changes in subchondral bone, cartilage, osteophyte, and synovitis were assessed using micro–computed tomography, tartrate-resistant acid phosphatase staining, pathologic section staining, and immunohistochemistry at 1, 2, 4, and 8 weeks. Results: At 1, 2, and 4 weeks, the OA limb had lower mean footprint pressure intensity, lower bone volume per tissue volume (BV/TV) in the subchondral bone, and more osteoclasts. At 4 weeks, the early loading, ALN, and load + ALN treatments induced less cartilage destruction, with a corresponding reduction in Osteoarthritis Research Society International score and increased hyaline cartilage thickness. The treatments also resulted in fewer osteoclasts and higher BV/TV and bone mineral density of subchondral bone and suppressed inflammation and interleukin 1β– and tumor necrosis factor α-positive cells in synovium. At 8 weeks, early loading or load + ALN improved the mean footprint pressure intensity and knee flexion. At 8 weeks, early load + ALN had a synergistic effect on protecting hyaline cartilage and proteoglycans. Footprint pressure intensity and cartilage destruction were worse in late loading limbs, and no differences in BV/TV, bone mineral density, osteophyte formation, and synovium inflammation were found between the late load, ALN, and load + ALN groups and the anterior cruciate ligament transection group. Conclusion: Dynamic axial mechanical loading or ALN in the early stages of knee trauma protected against OA by suppressing subchondral bone remodeling. However, late loading promoted cartilage degeneration in advanced OA, indicating that reduced loading should be performed in the late stages of OA to avoid the acceleration of OA. Clinical Relevance: Early low-level functional exercise or antiosteoporotic drugs could clearly slow or prevent the progression of early OA. For patients with mild to severe OA, loading reduction via brace protection or maintenance of joint stability via early ligament reconstruction surgery may ameliorate OA exacerbation.

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“…Engdahl et al demonstrated that global or cartilage‐specific inactivation of ERα did not increase the severity of antigen‐induced arthritis 57 . Interestingly, osteoblast‐specific ERα knockout did not affect cartilage health but promoted more severe cartilage damage when animals were subjected to 2 weeks of cyclic tibial loading 58 . Therefore, it will be interesting to study how depleting ERα in cartilage will affect disease severity and progression in the mechanical injury‐induced osteoarthritis model.…”

Section: Discussionmentioning

confidence: 99%

In vitro study to identify ligand‐independent function of estrogen receptor‐α in suppressing DNA damage‐induced chondrocyte senescence

et al. 2023

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In osteoarthritis (OA), chondrocytes undergo many pathological alternations that are linked with cellular senescence. However, the exact pathways that lead to the generation of a senescence‐like phenotype in OA chondrocytes are not clear. Previously, we found that loss of estrogen receptor‐α (ERα) was associated with an increased senescence level in human chondrocytes. Since DNA damage is a common cause of cellular senescence, we aimed to study the relationship among ERα levels, DNA damage, and senescence in chondrocytes. We first examined the levels of ERα, representative markers of DNA damage and senescence in normal and OA cartilage harvested from male and female human donors, as well as from male mice. The influence of DNA damage on ERα levels was studied by treating human chondrocytes with doxorubicin (DOX), which is an often‐used DNA‐damaging agent. Next, we tested the potential of overexpressing ERα in reducing DNA damage and senescence levels. Lastly, we explored the interaction between ERα and nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) pathway. Results indicated that the OA chondrocytes contained DNA damage and displayed senescence features, which were accompanied by significantly reduced ERα levels. Overexpression of ERα reduced the levels of DNA damage and senescence in DOX‐treated normal chondrocytes and OA chondrocytes. Moreover, DOX‐induced the activation of NF‐κB pathway, which was partially reversed by overexpressing ERα. Taken together, our results demonstrated the critical role of ERα in maintaining the health of chondrocytes by inhibiting DNA damage and senescence. This study also suggests that maintaining the ERα level may represent a new avenue to prevent and treat OA.

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Low bone mass resulting from impaired estrogen signaling in bone increases severity of load-induced osteoarthritis in female mice

Cited by 16 publications

References 61 publications

Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α

Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α

Axial Compressive Loading Attenuates Early Osteoarthritis by Reducing Subchondral Bone Remodeling

In vitro study to identify ligand‐independent function of estrogen receptor‐α in suppressing DNA damage‐induced chondrocyte senescence

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