Calcium is the major regulator of keratinocyte differentiation in vivo and in vitro. A calcium gradient within the epidermis promotes the sequential differentiation of keratinocytes as they traverse the different layers of the epidermis to form the permeability barrier of the stratum corneum. Calcium promotes differentiation by both outside–in and inside–out signaling. A number of signaling pathways involved with differentiation are regulated by calcium, including the formation of desmosomes, adherens junctions and tight junctions, which maintain cell–cell adhesion and play an important intracellular signaling role through their activation of various kinases and phospholipases that produce second messengers that regulate intracellular free calcium and PKC activity, critical for the differentiation process. The calcium receptor plays a central role by initiating the intracellular signaling events that drive differentiation in response to extracellular calcium. This review will discuss these mechanisms.

IMPORTANCE The aging of the population is associated with an increasing burden of fractures worldwide. However, the epidemiological features of fractures in mainland China are not well known. OBJECTIVE To assess the prevalence of and factors associated with osteoporosis, clinical fractures, and vertebral fractures in an adult population 40 years or older in mainland China. DESIGN, SETTING. AND PARTICIPANTS This cross-sectional study, the China Osteoporosis Prevalence Study, was conducted from December 2017 to August 2018. A random sample of individuals aged 20 years or older who represented urban and rural areas of China were enrolled, with a 99% participation rate. MAIN OUTCOMES AND MEASURES Weighted prevalence of osteoporosis, clinical fracture, and vertebral fracture by age, sex, and urban vs rural residence as determined by x-ray absorptiometry, questionnaire, and radiography. RESULTS A total of 20 416 participants were included in this study; 20 164 (98.8%; 11 443 women [56.7%]; mean [SD] age, 53 [13] years) had a qualified x-ray absorptiometry image and completed the questionnaire, and 8423 of 8800 (95.7%) had a qualified spine radiograph. The prevalence of osteoporosis among those aged 40 years or older was 5.0% (95% CI, 4.2%-5.8%) among men and 20.6% (95% CI, 19.3%-22.0%) among women. The prevalence of vertebral fracture was 10.5% (95% CI, 9.0%-12.0%) among men and 9.7% (95% CI, 8.2%-11.1%) among women. The prevalence of clinical fracture in the past 5 years was 4.1% (95% CI, 3.3%-4.9%) among men and 4.2% (95% CI, 3.6%-4.7%) among women. Among men and women, 0.3% (95% CI, 0.0%-0.7%) and 1.4% (95% CI, 0.8%-2.0%), respectively, with osteoporosis diagnosed on the basis of bone mineral density or with fracture were receiving antiosteoporosis treatment to prevent fracture. CONCLUSIONS AND RELEVANCEIn this cross-sectional study of an adult population in mainland China, the prevalence of osteoporosis and vertebral fracture were high and the prevalence of vertebral fracture and clinical fracture was similarly high in men and women. These findings suggest that current guidelines for screening and treatment of fractures among patients in China should focus equally on men and women and should emphasize the prevention of vertebral fractures.

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and impairing differentiation in keratinocytes (8). One of the immediate cellular responses to Ca 2ϩo in epithelial cells is the formation of cell-cell contacts, a process mediated by the adhesion molecule E-cadherin (10). E-cadherin is a major classical cadherin in keratinocytes and is expressed throughout the epidermis (11). Upon Ca 2ϩ o stimulation, the extracellular portion of E-cadherin interacts with E-cadherin molecules on the surface of neighboring cells, whereas its cytoplasmic tail interacts with ␤-(or ␥-), ␣-, and p120-catenins to form the core adhesive structure of adherens junctions (AJ) (12). E-cadherin-mediated cell adhesion plays key roles in remodeling of epithelial cell-cell interaction and maintaining proper epidermal differentiation (10, 13). Loss of E-cadherin in the epidermis leads to a loss of AJ and impaired terminal differentiation (14). The sequential binding of catenins physically links E-cadherin to the actin cytoskeleton and other signaling molecules, including phosphatidylinositol 3-kinase (PI3K) (10, 15). Keratinocyte differentiation induced by Ca 2ϩ o necessitates the activation of PI3K. Pharmacological inhibition of PI3K blocks the expression of late differentiation markers and induces apoptosis in differentiating keratinocytes (16,17). Through interactions with the E-cadherin-catenin complex PI3K is recruited to the cell membrane, where it converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate in turn binds and activates PLC␥1 (17), which is required for maintaining the Ca Veterans Affairs and Grants PO1-AR39448, RO1-AR38386, and RO1-AG21353 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom correspondence should be addressed: Endocrine Unit (111N