Santina Conte, MD1; Vu Le, MD, FRCSC2; Monica K. Li, MD, FRCPC, FAAD3

1Division of Dermatology, McGill University, Montréal, QC, Canada
2Department of Orthopaedics, University of British Columbia, Vancouver, BC, Canada
3Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflicts of interest: The authors have no relevant conflicts of interest to disclose. Funding sources: None.

ABSTRACT
The skin’s role as a mirror of internal disease has long been established, with clear associations to several internal organs. However, its relationship with bone is less well known. There are clear physiological links between the two organ systems, with their shared factors crucial to maintain structural integrity and homeostasis. Collagen, vitamin D homeostasis, aging, medications, and the gut microbiome are all factors that impact both skin and bone. It is of utmost importance that the skin-bone axis be adequately understood to support a healthy aging process. In this review, we discuss the multiple facets related to skin and bone health, their interconnectivity, as well as the importance of promoting whole body health.

Keywords: skin, bone, skin-bone axis, crosstalk, aging

Introduction

The skin has long been regarded as a mirror of internal disease, with cutaneous features sometimes presenting as the first manifestation of internal pathology.1,2 While the skin’s relationship to several internal organs is well established, its association with the skeletal system, namely bone, is less well known. While seemingly different at first glance, skin and bone are actually closely related; in early human development, dermis and bone are thought to originate from a common primordial mesenchyme.3 Other similarities are also present at the cellular level, allowing for both skin and bone turnover. Langerhans cells of the skin and osteoclasts (bone) are both derived from the monocyte/macrophage line of hematopoietic stem cells, and the two tissues share several cytokines involved in cell turnover, namely Wnt, receptor activator of nuclear factor-kappa B ligand (RANKL) and bone morphogenetic proteins (BMP).3-10 Most importantly, collagen is a fundamental component of both tissues,11-13 which can be modified by several factors: aging, drugs (e.g. glucocorticoids), metabolic diseases (e.g. diabetes), inflammation and hormones (e.g. estrogen).14-23 Clinically, several dermatoses are associated with skeletal pathology, such as psoriasis and psoriatic arthritis, palmoplantar pustulosis and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis), as well as small vessel vasculitides and their associated arthralgias, reinforcing the link between these two systems. A recent review by Morimoto et al. discussed the skin-bone axis, alluding to the idea of crosstalk between the two organ systems.24 This review discusses several perspectives relating to both skin and bone health, as well as links between the two.

Aging’s Impact on Skin and Bones

Similar mechanisms are at the heart of both skin and bone aging, including cellular senescence, oxidative stress, and impaired extracellular matrix (ECM) remodelling.25-28 Skin aging is characterized by skin laxity, wrinkles, textural changes and pigmented or vascular lesions.25 Age-related changes are driven by intrinsic and extrinsic factors, notably hormonal fluctuations, genetic predisposition and cellular senescence (intrinsic factors), as well as ultraviolet radiation, air pollution, smoking (via the production of reactive oxygen species) and poor nutrition (extrinsic factors).26,29 Collagen fibres (primarily types I and III) make up the majority of the cutaneous extracellular matrix, alongside elastic fibres, glycosaminoglycans, proteoglycans and fibronectin.30 As individuals age, the quantity of dermal collagen decreases, in addition to becoming fragmented and coarsely distributed, which in turn negatively impacts the interaction between fibroblasts and the ECM, further decreasing total dermal collagen and thinning the skin.31 Meanwhile, other functional ECM components are also reduced, resulting in wrinkles and reduced elasticity.31

With regards to bone, increasing age results in skeletal microenvironment changes that favour bone resorption and inhibit bone formation, as well as bone marrow fat accumulation and cellular senescence.28 Osteoblasts succumb to increased apoptosis, decreased quantities and limitations in function, including impaired mechanical sensing, intercellular modulation and exosome secretion, whereas osteoclastic activity is enhanced.28 The decrease in bone mass increases an individual’s fracture risk.32 Moreover, there is a notable loss in bone quality, likely due to changes in the quality of the mineral crystals, which also increases the risk of fracture.33,34 Non-enzymatically-mediated collagen cross-linking increases, resulting in stiffer bones that can also be more brittle and likely to break.33 Water bound to bone collagen or mineral declines with age, contributing to skeletal fragility by reducing a bone’s deforming potential before fracturing.33 As in skin, collagen is also of utmost importance in bone. As the primary organic component of the bone matrix, it is essential for bone strength, structural integrity and mineralization, as well as playing a crucial role in the regulation of bone cell activity through osteoblasts, osteoclasts and osteocytes.35 Age-related changes in collagen (e.g. increased advanced glycation end products) can impair bone toughness and increase fracture risk, regardless of an individual’s bone mineral density.13,36 Moreover, disorders of collagen can impact both skin and bone. Examples include Ehlers-Danlos syndrome (EDS), osteogenesis imperfecta (OI) and COL1-related overlap disorder. In EDS, patients present with both skin and joint hyperextensibility, as well as atrophic scars.37 Patients with OI have notable bone fragility, recurrent fractures, skeletal deformity and blue sclerae, as well as skin thinning, easy bruising and impaired wound healing.38 COL-1 related overlap disorder features elements of both EDS and OI, with predominant EDS features (severe joint hyperlaxity, skin hyperextensibility, abnormal wound healing) and mild OI features (blue sclerae, short stature, osteopenia).38

Overall, age-related changes in collagen, namely fragmentation, reduced synthesis, altered cross-linking, and accumulation of advanced glycation end products, directly contribute to the decline of both skin and bone.33,39,40 Studies have reported an association between skin thickness and bone mineral density, hypothesizing that the degree of skin alterations from aging could help in estimating age-related bone changes.41

Skin-Bone Communication Pathways

Skin and bone influence one another via bidirectional endocrine and metabolic signals transmitted by the substances that they each secrete into the bloodstream, promoting optimal health of both tissues.24 The primary means by which the two systems communicate is through collagen synthesis, inflammatory signalling and hormonal regulation.24

The skin influences bone health in one of three ways: vitamin D metabolism, cystatin A secretion, or oral fibroblasts’ paracrine activity (Table 1). Vitamin D acts as the dominant communication pathway between skin and bone by mediating cutaneous vitamin D synthesis to skeletal homeostasis via multiple modes of cell signalling.42 After exposure to ultraviolet B radiation, the vitamin D3 (cholecalciferol) is synthesized in the skin.42-44 It is then hepatically converted to 25-hydroxyvitamin D, and finally reaches its active form, 1,25-dihydroxyvitamin D in the kidneys and other tissues (including bone and skin).42-44 This active form is able to regulate gene transcription involved in keratinocyte differentiation, epidermal barrier function, osteoblast maturation, matrix production, and mineralization after binding to vitamin D receptors in the skin and bone.43,45,46 Vitamin D receptor signalling in the skin and bone also regulates calcium and phosphate homeostasis, immune modulation and tissue remodelling – all of which impact skin integrity and bone strength.47-49 In turn, vitamin D deficiency, which can occur in the context of aging or inadequate sun exposure limiting its cutaneous synthesis, results in both impaired epidermal function and increased risk of osteoporosis and fractures.50-52 Moreover, vitamin D decreases chronic inflammation affecting both skin and bone by acting as an immunoregulatory mediator of inflammatory cytokines and immune signals within the skin-bone axis.52,53

Table 1:

More Than Skin Deep: Understanding the Skin-Bone Axis - image

Cystatin A is keratinocyte-enriched secreted small protein capable of inhibiting cysteine proteases, mediating the effect of skin on bone.54,55 As it binds to its receptor in osteoblast and osteoclast progenitors, it promotes their proliferation but inhibits osteoclast differentiation.55 As we age, the skin secretes less cystatin A, which in turn contributes to senile osteoporosis; in other words, age-related epidermal thinning and bone thinning occur simultaneously.55

The final means by which the skin impact bone is via oral fibroblast activity. Oral fibroblasts secrete trophic factors and proteins primarily involved in the transforming growth factor-beta (TGF-β) pathway, which in turn are responsible for osteogenic differentiation of mesenchymal stem cells and bone formation, as well as rescuing or enhancing local progenitor cells’ osteogenic potential and influencing bone repair and regeneration.56

Impact & Association of Skin Diseases with Bone Health

Several factors related to skin diseases can impact bone health, especially in the context of inflammatory dermatoses such as psoriasis, lupus and vesiculobullous disorders. Inflammatory skin diseases are linked to heightened risk of osteopenia, osteoporosis and fractures due to heightened inflammation, vitamin D deficiency, immune dysregulation, and medications (e.g. corticosteroids).52,57 Chronic inflammation results in systemic immune activation, disrupting the balance between bone formation and bone resorption due to elevated pro-inflammatory cytokines (e.g. tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, IL-17) and resulting in heightened osteoclastogenesis.58,59 IL-17A is thought to act as the key mediator, suppressing bone formation through inhibition of Wnt signalling.60 Other pro-inflammatory cytokines that create the pro-osteoclastogenic environment include IL-33, osteopontin and TNF-α released from inflamed skin, which induce RANKL and promote the production of active osteoclasts.61 Vitamin D, important for calcium homeostasis and bone mineralization, can be depleted in skin conditions that limit sun exposure (e.g. photodermatoses, severe eczema) or impair vitamin D synthesis (e.g. vitiligo), resulting in bone fragility.59 Independent of the inflammatory nature of these chronic dermatoses, the therapies used in their management also promote osteoporosis. Corticosteroids suppress osteoblast activity and increase osteoclastogenesis, inducing osteoporosis, which is a well-recognized side effect.58,59 Notably, according to the 2022 American Academy of Dermatology Guidelines for comorbidities associated with atopic dermatitis, fracture prevention therapy should be initiated in patients with heightened fracture risk, e.g. oral corticosteroid use with cumulative dose equivalent to ≥3 months of ≥5-7.7.5 mg daily of prednisone.62 Similarly, there is a clear dose-response relationship between cumulative exposure to potent/very potent topical corticosteroids and risk of osteoporosis/ major osteoporotic fractures in a dose-dependent manner.63 Low-dose methotrexate, such as doses used in dermatology to treat inflammatory dermatoses, has not been found to have an adverse effect on bone metabolism.64 Studies related to cyclosporine did not measure bone mineral density, but overall reported a reduction in erosions and joint damage with no clinically significant adverse effects on bone.65 Biologic therapies (e.g. TNF-α, IL-17, IL-12/23) reduce markers of bone turnover and overall demonstrate protective effects on bone health.65,66 Peripheral computed tomography studies of patients with psoriatic arthritis treated with biologic therapy noted significantly higher total and trabecular volumetric bone mineral density and greater bone strength (failure load and stiffness) despite longer overall disease duration.67 Such changes are thought to be due to reduction in systemic inflammation with effect on generalized and localized bone loss, resulting in slowing of progression of bone erosion.68

Cutaneous Manifestations of Bone Pathologies

Bone pathologies with cutaneous manifestations can occur in either autoinflammatory or metabolic bone diseases (Table 2). Autoinflammatory bone diseases include disorders such as chronic recurrent multifocal osteomyelitis (CRMO) and SAPHO syndrome. In both conditions, cutaneous features often present before bone involvement, reinforcing their importance in early diagnosis.69 Acne, papules and pustules are the most common cutaneous features, and may contribute to the severity of inflammation in the underlying autoinflammatory bone disease.69 Cutibacterium acnes (C. acnes), a commensal organism of skin microbiota most common in sebaceous gland-rich areas, has been increasingly recognized to be associated with CRMO and SAPHO. While CRMO is classically considered to be an aseptic inflammatory condition, C. acnes has been isolated from bone biopsy specimens in a subset of patients with autoinflammatory bone disorders (49% as per a recent study).70 Thus, C. acnes could be a link between cutaneous and osseous manifestations in autoinflammatory bone disorders, perhaps by acting as a contributory or triggering factor or reflecting an underlying genetic or immunologic impairment in bacterial clearance in affected individuals.

Table 2:

More Than Skin Deep: Understanding the Skin-Bone Axis - image

With regards to metabolic bone diseases, cutaneous features are noted in conditions such as calcinosis cutis, osteoma cutis and certain parathyroid-based disorders. In calcinosis cutis, abnormal calcium and/or phosphate metabolism results in metastatic calcium deposition in the skin and subcutis, while individuals with normal serum calcium and phosphate can have dystrophic calcification following local tissue damage.71 Osteoma cutis occurs in one of two contexts: either when dermal mesenchymal cells transform into osteoblasts (primary osteoma cutis) or in the presence of dystrophic ossification in damaged or inflamed tissue (secondary osteoma cutis).72 Parathyroid-related disorders, as well as familial hyperparathyroidism syndromes, also have diverse cutaneous and adnexal features. Hyperparathyroidism associated with renal failure presents with metastatic calcification that can be accompanied by infections and necrosis.73 Hypoparathyroidism commonly manifests with dry, scaly, puffy skin with brittle nails and coarse, sparse hair.74 With regards to familial hyperparathyroidism syndromes, multiple endocrine neoplasia 1 (MEN 1) commonly presents with angiofibromas, collagenomas, lipomas and café au lait spots, whereas cutaneous amyloidosis is a feature of multiple endocrine neoplasia 2a.73

Links Between Gut Microbiome to Bone Health to Skin Microbiome

Immunological, metabolic and endocrine pathways interconnect bone health and skin and gut microbiomes. The gut microbiome regulates intestinal permeability and systemic inflammation, thereby contributing to bone homeostasis through nutrient absorption and conditions such as osteoporosis, rheumatoid arthritis, osteoarthritis and periodontitis.75-77 Similarly, the gut and skin microbiomes are also intertwined, whereby the skin microbiome can interact with the immune system and produce systemic inflammation. The “gut-skin axis” has also been previously established, where gut-derived metabolites and immune mediators can affect skin barrier function and inflammation, and vice versa. Bone remodelling and turnover can be impacted by chronic inflammation originating from either the gut or skin, reinforcing the existence of the skin-bone axis.52,75,78 Gut microbiome dysbiosis is thought to compromise both skin and bone via dysfunction of the intestinal barrier, increased inflammatory mediators and secreted metabolites.24 Overall, the factors causing gut microbiome dysbiosis, including genetic predisposition, aging, drugs, diet, alcohol consumption, and smoking also negatively impact skin and bone health, leaving us to hypothesize that skin and bone pathologies may share common etiologies or pathologies originating in the gut microbiome.79,80

Value of a Multidisciplinary, Holistic Model to Improve the Aging Process

The associations between aging skin and bone health are multifold. At the heart of their connection are their shared pathophysiological mechanisms, namely collagen degradation, vitamin D deficiency, oxidative stress, and chronic inflammation. Nutritional and lifestyle interventions have the potential to provide synergistic benefits for both. For instance, adequate protein, calcium and vitamin D intake supports both dermal collagen synthesis and bone mineralization, while antioxidant-rich nutrients (e.g. polyphenols, vitamins C and E) offset oxidative stress in both tissues.81,82 Physical activity, especially in the form of resistance and weight-bearing exercises, improves skin microcirculation, stimulates osteoblast activity thereby improving bone quality, and enhances muscle function, which in turn protects both skin (by reducing trauma) and bone (decreasing injury and associated fractures).83,84 Aging mechanisms that impact both skin and bone, including glucocorticoids, diabetes, chronic inflammation and estrogen deficiency should also be targeted by means of vitamin D supplementation, anti-inflammatory diets and adequate control of underlying metabolic conditions. Finally, multidisciplinary medical care is key in providing comprehensive assessment and treatment. For instance, dermatologists can identify skin changes that may be representative of underlying bone fragility or be cognisant of osteopenia-inducing medical treatments, while endocrinologists and geriatricians can screen for osteoporosis in patients with chronic inflammatory skin conditions. This multidisciplinary team-based approach can optimize patient care and reinforce the importance of the skin-bone axis throughout the aging process (Table 3).

Table 3:

More Than Skin Deep: Understanding the Skin-Bone Axis - image

Conclusion

Overall, the importance of the skin-bone axis should not be underestimated. There are clear physiological links between the two organ systems, with interrelated factors in both to maintain structural integrity and homeostasis. The two influence each other’s function in health, aging and disease by means of overlapping extracellular matrix components, endocrine signalling, immune modulation and mechanotransduction, with impairment of one of these domains resulting in pathology in both tissues. A proper understanding of the interconnectivity of skin and bone will allow physicians to better treat patients, promoting whole-body health and supporting the aging process.

 

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STL Volume 31 Number 4
STL Volume 31 Number 4

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