Osteoarthritis: Insights Offered by the Study of Bone Mass Genetics

Abstract Purpose of Review This paper reviews how bone genetics has contributed to our understanding of the pathogenesis of osteoarthritis. As well as identifying specific genetic mechanisms involved in osteoporosis which also contribute to osteoarthritis, we review whether bone mineral density (BMD) plays a causal role in OA development. Recent Findings We examined whether those genetically predisposed to elevated BMD are at increased risk of developing OA, using our high bone mass (HBM) cohort. HBM individuals were found to have a greater prevalence of OA compared with family controls and greater development of radiographic features of OA over 8 years, with predominantly osteophytic OA. Initial Mendelian randomisation analysis provided additional support for a causal effect of increased BMD on increased OA risk. In contrast, more recent investigation estimates this relationship to be bi-directional. However, both these findings could be explained instead by shared biological pathways. Summary Pathways which contribute to BMD appear to play an important role in OA development, likely reflecting shared common mechanisms as opposed to a causal effect of raised BMD on OA. Studies in HBM individuals suggest this reflects an important role of mechanisms involved in bone formation in OA development; however further work is required to establish whether the same applies to more common forms of OA within the general population.

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Increased development of radiographic hip osteoarthritis in individuals with high bone mass: a prospective cohort study

Arthritis Research & Therapy ◽

10.1186/s13075-020-02371-0 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

April Hartley ◽

Sarah A. Hardcastle ◽

Monika Frysz ◽

Jon Parkinson ◽

Lavinia Paternoster ◽

...

Keyword(s):

Bone Mass ◽

Functional Limitations ◽

Functional Limitation ◽

Hip Osteoarthritis ◽

Joint Space ◽

Mineral Density ◽

High Bone Mass ◽

High Bone ◽

Subchondral Sclerosis

Abstract Background Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes. Methods We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering. Results Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM βosteophyte = 0.30 [0.01, 0.58], p = 0.019 and βJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (β = 8.3 [0.7, 15.98], p = 0.032). Conclusions HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.

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High bone mass gained by exercise in growing male mice is increased by subsequent reduced exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.01169.2003 ◽

2004 ◽

Vol 97 (3) ◽

pp. 806-810 ◽

Cited By ~ 27

Author(s):

Jian Wu ◽

Xin Xiang Wang ◽

Mitsuru Higuchi ◽

Kazuhiko Yamada ◽

Yoshiko Ishimi

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mass ◽

Exercise Group ◽

Mineral Apposition Rate ◽

Male Mice ◽

Sedentary Control ◽

Mineral Density ◽

High Bone Mass ◽

High Bone

Exercise-induced bone gains are lost if exercise ceases. Therefore, continued exercise at a reduced frequency or intensity may be required to maintain these benefits. In this study, we evaluated whether 4 wk of reduced exercise after 4 wk of running exercise in growing male mice results in the maintenance of high bone mass. Five-week-old mice were divided into the following groups: 1) baseline control; 2) 4-wk control; 3) 4-wk exercise; 4) 8-wk control; 5) 4-wk exercise followed by 4-wk cessation of training; and 6) 4-wk exercise followed by reduced exercise at half the frequency. The regimen consisted of exercise 6 days/wk, and the reduced exercise regimen consisted of running 3 days/wk on a treadmill for 30 min/day, at 12 m/min on a 10° uphill slope. Running exercise significantly increased bone mineral density of the femur, periosteal mineral apposition rate, bone formation rate, percent labeled perimeter at the midfemur, and osteogenic activity of bone marrow cells. However, these parameters declined to the age-matched sedentary control after cessation of training. In contrast, the reduced exercise group had significantly higher mineral apposition rate compared with those of the sedentary control and cessation of training groups. Furthermore, bone mineral density for the reduced exercise group was significantly higher than those for the other groups. These results suggest that the high bone formation gained through exercise can be maintained, and bone mass was further increased by subsequent exercise even if the exercise frequency is reduced.

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Role of CaMKK2 in Osteocytes within the Bone Microenvironment

Proceedings of IMPRS ◽

10.18060/22676 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Nick Clough ◽

Justin Williams ◽

Uma Sankar

Keyword(s):

Bone Mass ◽

Bone Cell ◽

T Antigen ◽

Dendritic Morphology ◽

Bone Biology ◽

High Bone Mass ◽

High Bone ◽

High Bone Mass Phenotype ◽

Outstanding Question

Background and Hypothesis: The Ca+2/calmodulin (CaM)-mediated protein kinase kinase 2 (CaMKK2) is a multi-functional kinase with effects on cell proliferation, differentiation and metabolism. The role of CaMKK2 in bone has been explored with its ablation favoring osteoblasts to osteoclasts and bone mass accrual as observed in Camkk2-/- mice, or following its inhibition by STO-609. One outstanding question is whether the anabolic effects of CaMKK2 are bone-cell intrinsic. While analyzing mice harboring bone-cell specific deletion of CaMKK2, we observed a high bone mass phenotype when the kinase is deleted from osteocytes, the most abundant cells within the bone. We therefore hypothesized that the loss of CaMKK2 enhances osteocyte differentiation. Experimental Design or Project Methods: We used two osteocyte cell lines MLO-Y4 and MLO-A5, both generated from mice expressing the immortalizing T-antigen, to test our hypothesis. The MLO-A5 line has post-osteoblast/pre-osteocyte characteristics while the MLO-Y4 line has mature osteocyte characteristics. CaMKK2 expression was silenced in MLO-A5 cells using Lentiviruses encoding CaMKK2 short hairpin (sh) RNA constructs. STO-609 was employed to inhibit CaMKK2 in the MLO-Y4 line as it proved resistant to transfection. Immunoblotting was used to verify CaMKK2 silencing/inhibition. Comparisons on cell morphologies were observed using immunofluorescence. As osteocytes are defined by dendritic morphology, the number of dendritic processes were analyzed. Additionally, the differences in the expression of the osteocyte markers SOST, E11 and DMP1 were examined by qRT-PCR. Results: To be finalized. Conclusion and Potential Impact: Overall, our studies will provide more information towards understanding the role of CaMKK2 in bone biology and aid its development as a therapeutic target in the treatment of osteoporosis.

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SAT0469 PROSPECTIVE STUDY ASSESSING BONE MINERAL DENSITY AND RISK FACTORS FOR OSTEOPOROSIS IN PATIENTS WITH ANDROGEN DEPRIVATION THERAPY. PRELIMINARY CROSS-SECTIONAL RESULTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5204 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1192.2-1192

Author(s):

L. Gifre ◽

F. Elias ◽

P. Servian ◽

R. Freixa ◽

O. Buisan Rueda

Keyword(s):

Risk Factors ◽

Bone Mineral Density ◽

Bone Mass ◽

Prospective Study ◽

Fragility Fractures ◽

Mineral Density ◽

High Bone Mass ◽

Cross Sectional ◽

X Ray ◽

High Bone

Background:Few studies have analysed the incidence and risk factors for osteoporosis (OP) development in patients with prostate cancer (PC) and androgen deprivation therapy (ADT).Objectives:To assess risk factors for OP, bone turnover markers (BTM) and bone mineral density (BMD) in a cohort of patients with ADT, as well as the duration of ADT and previous treatments received for PC.Methods:Ongoing prospective study including patients with ADT for PC. Risk factors for OP, BTM (total ALP, bone ALP, CTx), spinal X-Ray and BMD (Lunar, DPX) were assessed yearly since inclusion in the study (April 2018). Patients with known OP or previous antiosteoporotic treatment were excluded. The study was approved by the ethics committee, and all patients gave their signed consent. Herein we present the preliminary cross-sectional study at inclusion.Results:Of the 83 patients attended at the Rheumatology Department during the study period, 75 were included with a mean age 75±5years and median ADT duration of 1 year. 18 were receiving concomitant radiotherapy and 7 docetaxel.When assessing risk factors for OP: 28% had previous fragility fractures and 24% had current alcohol intake. After X-Ray assessment, 14% had morphometric vertebral fractures. Mean 25OHD at inclusion was 19±9ng/ml (73% had 25OHD <30ng/ml) and mean testosterone was 82±162ng/dL (75% had levels <50ng/dl). All patients had increased values of CTx and 9% had increased bone ALP levels.BMD showed up to 28% with densitometric OP and osteopenia in 56%. Patients with OP were older (83±7 vs 74±8 years, p=0.021), had lower testosterone levels (16 vs 89 ng/dl, p=0.004), as expected lower BMD (at spine, proximal femur and even distal radius) and had more previous fragility fracture (75 vs 19%, p=0.022). But it should be noted that 16% had high bone mass (HBM) mostly affecting spine BMD (in 6 patients combined with femoral osteopenia). All patients with HBM had high bone metastatic disease, and no differences were observed between patients with/without HBM when comparing BTM or calcium-phosphate metabolism.Conclusion:Low bone mass (including osteoporosis and osteopenia) is frequent in patients with ADT as well as previous fragility fractures. Up to 16% had high bone mass, being mostly in patients with high volume metastatic disease. Thus, all patients with ADT should undergo a bone health assessment and start antiosteoporotic treatment if required.Disclosure of Interests:None declared

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